{"gene":"CDCA8","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2008,"finding":"Borealin/CDCA8 (DasraB) is an essential component of the chromosomal passenger complex (CPC); genetic knockout in mice causes early embryonic lethality by 5.5 dpc due to mitotic defects, microtubule disorganization, absence of CPC enrichment, and p53-independent apoptosis in blastocyst cells.","method":"Targeted gene disruption (borealin-null mice), immunofluorescence for microtubule organization and CPC localization, genetic rescue by p53 deletion","journal":"Mechanisms of development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic epistasis (p53 rescue attempted), clean KO with defined cellular phenotype, multiple orthogonal methods (histology, immunofluorescence, genetic rescue), peer-reviewed","pmids":["18337066"],"is_preprint":false},{"year":2015,"finding":"Transcription factor NF-Y (via NF-YA subunit) and CREB1 directly bind cis-elements in the CDCA8 basic promoter to activate transcription; NF-Y overexpression enhances and NF-Y knockdown reduces CDCA8 transcription. The NF-YA subunit that binds the promoter is primarily a short isoform in hESCs and a long isoform in cancer cells, indicating distinct activation mechanisms.","method":"Reporter gene assays, mutation analyses of promoter cis-elements, electrophoretic mobility shift assays (EMSA), NF-Y overexpression and knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (EMSA, reporter assays, mutagenesis, gain/loss-of-function), single lab but comprehensive study","pmids":["26170459"],"is_preprint":false},{"year":2020,"finding":"CDCA8 protein localizes dynamically from germinal vesicle breakdown (GVBD) to metaphase II in human oocytes; RNAi-mediated depletion of CDCA8 causes multipolar spindles, disordered chromosomes, and impaired microtubule assembly, with extended polar body extrusion time, establishing a role for CDCA8 in bipolar spindle formation and chromosome segregation during human oocyte meiosis.","method":"RNAi knockdown in GV-stage human oocytes, immunofluorescence for spindle and chromosome morphology, live imaging","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined spindle/chromosome phenotype, but single lab study","pmids":["32088244"],"is_preprint":false},{"year":2021,"finding":"CDCA8 silencing in hepatocellular carcinoma cells downregulates cyclin B1 and p-CDC2, induces G2/M arrest, increases tumor-suppressive ATF3 and GADD34 protein levels, and inactivates AKT/β-catenin signaling, suppressing cancer stem cell properties (sphere formation, CD133+ population).","method":"shRNA knockdown, flow cytometry, RNA sequencing, western blot, xenograft model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined molecular readouts (western blot, RNA-seq), in vivo xenograft validation, single lab","pmids":["33801424"],"is_preprint":false},{"year":2021,"finding":"CDCA8 synergizes with E2F1 to promote glioma cell proliferation and migration; gene microarray identified E2F1 as a biological partner of CDCA8.","method":"Gene microarray chip, in vitro and in vivo loss-of-function assays (proliferation, migration, apoptosis)","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, E2F1 interaction identified only by expression microarray without direct protein interaction confirmation","pmids":["33542211"],"is_preprint":false},{"year":2022,"finding":"EZH2 activates CDCA8 expression in prostate cancer through two mechanisms: (1) methyltransferase-dependent H3K27 trimethylation represses let-7b miRNA, relieving let-7b-mediated suppression of CDCA8 transcripts; (2) methyltransferase-independent recruitment of E2F1 to the E2F1 own promoter drives E2F1 self-activation, which then promotes CDCA8 transcription.","method":"Genome-wide chromatin assays (ChIP-seq), let-7b overexpression/knockdown, EZH2 catalytic mutant constructs, transcriptomic profiling","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide assays plus mechanistic dissection of methyltransferase-dependent and -independent arms, multiple orthogonal approaches in single rigorous study","pmids":["35094010"],"is_preprint":false},{"year":2019,"finding":"KIF18B binds to the promoter region of CDCA8 and transcriptionally activates CDCA8 expression in pancreatic ductal adenocarcinoma cells.","method":"ChIP assay (KIF18B binding to CDCA8 promoter), qRT-PCR, KIF18B knockdown","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP evidence for promoter binding, supported by knockdown phenotype, single lab","pmids":["31875977"],"is_preprint":false},{"year":2022,"finding":"CDCA8 forms a complex with SNAI2 (SLUG) transcription factor; the CDCA8/SNAI2 complex binds the CD44 promoter and activates CD44 transcription, promoting proliferation and invasion of pancreatic ductal adenocarcinoma.","method":"Co-immunoprecipitation (Co-IP), ChIP-qPCR (CDCA8/SNAI2 binding to CD44 promoter), dual-luciferase reporter assay, lentiviral knockdown","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ChIP-qPCR and reporter assay in single lab; multiple orthogonal methods","pmids":["36358852"],"is_preprint":false},{"year":2023,"finding":"CDCA8 stabilizes HIF1α in bladder cancer by competing with PTEN for AKT binding, displacing PTEN and activating the AKT/GSK3β signaling cascade that increases HIF1α protein stability. HIF1α in turn binds the CDCA8 promoter for transcriptional activation, forming a positive-feedback loop.","method":"Co-immunoprecipitation, western blot, PTEN displacement assay, ChIP for HIF1α at CDCA8 promoter, hypoxic cell survival assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for protein interactions plus ChIP for promoter binding, mechanistic loop proposed with supporting experiments, single lab","pmids":["37813876"],"is_preprint":false},{"year":2023,"finding":"NF-YA transcription factor upregulates CDCA8 expression in hepatocellular carcinoma, and CDCA8 knockdown suppresses the MEK/ERK pathway and inhibits expression of downstream targets TPM3, NECAP2, and USP13; CDCA8 knockdown attenuates NF-YA-mediated cell invasion.","method":"RNA sequencing, next-generation sequencing, qRT-PCR, western blot, NF-YA overexpression, orthotopic tumor model","journal":"Experimental hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq plus western blot validation and in vivo model, single lab","pmids":["36639822"],"is_preprint":false},{"year":2022,"finding":"CDCA8 knockdown in thyroid cancer cells reduces CDK1 levels, and CDK1 overexpression partially rescues the tumor-suppressive effects of CDCA8 knockdown, placing CDK1 downstream of CDCA8 in thyroid cancer progression.","method":"shRNA knockdown, CDK1 overexpression rescue, in vitro proliferation/apoptosis assays, in vivo xenograft","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by rescue experiment, supported by in vivo data, single lab","pmids":["35517403"],"is_preprint":false},{"year":2021,"finding":"miR-133b directly targets CDCA8 mRNA (validated by dual-luciferase reporter assay); miR-133b overexpression reduces CDCA8 protein and inhibits proliferation, invasion, and migration of lung adenocarcinoma cells, which is reversed by CDCA8 overexpression.","method":"Dual-luciferase reporter assay, qRT-PCR, western blot, CCK-8, scratch healing, Transwell assays","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct miRNA-target validation by luciferase reporter plus rescue experiment, single lab","pmids":["33971546"],"is_preprint":false},{"year":2022,"finding":"miR-133a-3p directly targets the 3'UTR of CDCA8 mRNA (validated by dual-luciferase reporter assay); miR-133a-3p overexpression reduces CDCA8 expression and suppresses proliferation, migration, and invasion of esophageal cancer cells, reversible by CDCA8 restoration.","method":"Dual-luciferase reporter assay, qRT-PCR, western blot, CCK-8, flow cytometry, Transwell assays","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter for direct targeting plus rescue functional experiments, single lab","pmids":["34117764"],"is_preprint":false},{"year":2023,"finding":"Let-7c-5p directly targets and negatively regulates CDCA8 mRNA (validated by dual-luciferase reporter and western blot); CDCA8 overexpression reverses the tumor-suppressive effects of let-7c-5p on HCC cells.","method":"Dual-luciferase reporter assay, western blot, CCK-8, Transwell, wound healing, flow cytometry, rescue experiment","journal":"Functional & integrative genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation by luciferase reporter plus functional rescue, single lab","pmids":["36737507"],"is_preprint":false},{"year":2023,"finding":"TMED3 physically interacts with CDCA8 (co-immunoprecipitation); CDCA8 mediates the oncogenic effects of TMED3 in malignant melanoma by activating PI3K/AKT signaling; CDCA8 overexpression rescues the inhibitory effects of TMED3 knockdown, and CDCA8 knockdown suppresses P-AKT and P-PI3K levels.","method":"Co-immunoprecipitation, western blot, siRNA knockdown, SC79 (AKT activator) rescue, in vitro and in vivo assays","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for interaction plus epistasis by rescue experiments, single lab","pmids":["36991473"],"is_preprint":false},{"year":2025,"finding":"CDCA8 knockdown in oral squamous cell carcinoma reduces CDK1 and CDK2 levels; CDK1 inhibitor RO3306 phenocopies CDCA8 knockdown, and CDK1 overexpression reverses the growth-suppressive effect of CDCA8 knockdown, establishing CDK1 as a downstream effector of CDCA8.","method":"shRNA knockdown, CDK1 inhibitor (RO3306), CDK1 overexpression rescue, KEGG pathway analysis, in vivo xenograft","journal":"Discover oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic/pharmacological epistasis with rescue, in vivo confirmation, single lab","pmids":["41091302"],"is_preprint":false},{"year":2026,"finding":"USP35 deubiquitinase directly interacts with CDCA8 (validated by Co-IP) and removes ubiquitin chains from CDCA8, stabilizing the protein and preventing proteasomal degradation; USP35 knockdown reduces CDCA8 protein levels and inhibits NSCLC cell proliferation, migration, and invasion.","method":"Co-immunoprecipitation, IP-western blot for ubiquitination, cycloheximide chase assay, siRNA knockdown","journal":"Combinatorial chemistry & high throughput screening","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction plus ubiquitination IP and protein stability assay, single lab","pmids":["42002994"],"is_preprint":false},{"year":2026,"finding":"HAUS1 physically interacts with EZH2 and facilitates recruitment of E2F1 to the CDCA8 promoter via a methylation-independent HAUS1-EZH2-E2F1 axis, thereby transcriptionally activating CDCA8; CDCA8 loss abrogates oncogenic effects of HAUS1 overexpression in colorectal cancer.","method":"Co-immunoprecipitation (HAUS1-EZH2), ChIP for E2F1 at CDCA8 promoter, transcriptomic profiling, CDCA8 rescue/knockdown epistasis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus transcriptomic profiling plus genetic epistasis, single lab","pmids":["41546483"],"is_preprint":false},{"year":2026,"finding":"The 5'UTR of INCENP and 3'UTR of CDCA8 undergo m6A methylation (at specific GGACT motifs); YTHDF3 recognizes these m6A sites and facilitates translation of INCENP and CDCA8 through interaction with eIF3A; inhibition of INCENP and CDCA8 enhances chemotherapy sensitivity by promoting multipolar spindle formation.","method":"m6A sequencing/mapping, YTHDF3 binding assays, eIF3A interaction (Co-IP), multipolar spindle formation assay, functional chemosensitivity experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A mapping at defined positions plus YTHDF3/eIF3A co-IP and functional spindle assay, single study","pmids":["41565643"],"is_preprint":false},{"year":2026,"finding":"YBX1 directly binds CDCA8 mRNA and positively regulates CDCA8 expression; YBX1 overexpression promotes NSCLC cancer stem cell properties (SOX/NANOG expression, sphere formation, migration/invasion), and these effects are reversed by CDCA8 knockdown.","method":"RNA immunoprecipitation or binding assay (YBX1-CDCA8 mRNA), western blot, qRT-PCR, sphere-formation assay, Transwell, xenograft rescue","journal":"Neoplasma","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, binding method not fully detailed in abstract, functional rescue provided","pmids":["42054276"],"is_preprint":false},{"year":2023,"finding":"The 1-kb human CDCA8 promoter drives specific expression in GFRA1+ undifferentiated spermatogonia of adult mouse testis, as demonstrated in transgenic reporter mice, indicating that CDCA8 transcription is activated in early undifferentiated spermatogonia.","method":"Transgenic mouse luciferase reporter driven by 1-kb CDCA8 promoter, in vivo imaging, immunohistochemistry/immunofluorescence for luciferase co-localization with GFRA1","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic reporter mouse with direct imaging and IHC co-localization, clean experimental design, single lab","pmids":["36898512"],"is_preprint":false},{"year":2021,"finding":"MYBL2 is identified as an upstream transcription factor that positively regulates CDCA8 expression in ovarian cancer; silencing of CDCA8 sensitizes ovarian cancer cells to olaparib and cisplatin by inducing G2/M arrest, increasing DNA damage, and interfering with RAD51 accumulation.","method":"Transcription factor binding analysis, CDCA8 knockdown, flow cytometry (G2/M arrest), DNA damage assays (γH2AX), RAD51 foci immunofluorescence, drug sensitivity assays","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular assays with defined molecular readouts (RAD51, DNA damage), MYBL2-CDCA8 regulatory link supported, single lab","pmids":["33575078"],"is_preprint":false}],"current_model":"CDCA8 (Borealin/DasraB) is an essential subunit of the Chromosomal Passenger Complex (CPC) required for bipolar spindle formation, chromosome segregation, and cytokinesis in both mitosis and meiosis; its transcription is activated by NF-Y, CREB1, MYBL2, KIF18B, and the EZH2-E2F1 axis, its mRNA is negatively regulated by miR-133b, miR-133a-3p, and let-7 family members (with m6A-YTHDF3-eIF3A-mediated translational control also described), and its protein stability is maintained by the deubiquitinase USP35; downstream, CDCA8 promotes cell proliferation and survival through CDK1, MEK/ERK, AKT/GSK3β-HIF1α, and PI3K/AKT pathways, and also acts as a transcriptional co-activator (complexing with SNAI2 to drive CD44 expression), collectively making it a multifaceted regulator whose loss causes mitotic failure, apoptosis, and embryonic lethality."},"narrative":{"mechanistic_narrative":"CDCA8 (Borealin/DasraB) is an essential subunit of the Chromosomal Passenger Complex required for mitotic and meiotic fidelity: its loss causes microtubule disorganization, failure of CPC enrichment, p53-independent apoptosis, and early embryonic lethality in mice [PMID:18337066], and its depletion in human oocytes produces multipolar spindles, disordered chromosomes, and impaired microtubule assembly during meiosis [PMID:32088244]. The same spindle-organizing function underlies its requirement in cancer cells, where its expression is tightly controlled at multiple regulatory tiers. Transcriptionally, CDCA8 is activated by NF-Y/CREB1 binding to its basic promoter [PMID:26170459], by the EZH2–E2F1 axis acting through both H3K27me3-dependent repression of let-7b and methyltransferase-independent E2F1 self-activation [PMID:35094010, PMID:41546483], and by additional upstream factors including KIF18B and MYBL2 [PMID:31875977, PMID:33575078]. Post-transcriptionally, CDCA8 mRNA is repressed by miR-133b, miR-133a-3p, and let-7c-5p [PMID:33971546, PMID:34117764, PMID:36737507] and translationally enhanced through m6A modification read by YTHDF3 in concert with eIF3A [PMID:41565643], while its protein is stabilized against proteasomal degradation by the deubiquitinase USP35 [PMID:42002994]. Beyond its structural CPC role, CDCA8 acts as a transcriptional co-activator, forming a complex with SNAI2 (SLUG) to drive CD44 expression [PMID:36358852], and drives proliferation and survival through CDK1 [PMID:35517403, PMID:41091302] and through AKT-axis signaling, including PTEN displacement that stabilizes HIF1α in a positive-feedback loop [PMID:37813876]. A 1-kb CDCA8 promoter additionally drives expression in GFRA1+ undifferentiated spermatogonia, indicating activity in early germline cells [PMID:36898512].","teleology":[{"year":2008,"claim":"Established CDCA8/Borealin as an essential CPC component whose loss is incompatible with mitotic progression, defining its core cellular function.","evidence":"Targeted gene disruption in mice with immunofluorescence and genetic p53-deletion rescue","pmids":["18337066"],"confidence":"High","gaps":["Molecular basis of CPC enrichment defect not resolved at structural level","Does not address meiotic role","p53-independence of apoptosis leaves death mechanism unexplained"]},{"year":2015,"claim":"Identified the first direct transcriptional activators of CDCA8, showing NF-Y and CREB1 bind defined promoter cis-elements with isoform-specific activation in stem versus cancer cells.","evidence":"Reporter assays, promoter mutagenesis, EMSA, and NF-Y gain/loss-of-function","pmids":["26170459"],"confidence":"High","gaps":["Functional consequence of isoform switch on downstream phenotype unclear","Does not connect promoter activity to proliferation outcomes"]},{"year":2019,"claim":"Extended the transcriptional regulatory network by identifying KIF18B as a promoter-binding activator of CDCA8 in pancreatic cancer.","evidence":"ChIP, qRT-PCR, and KIF18B knockdown","pmids":["31875977"],"confidence":"Medium","gaps":["KIF18B is atypical as a transcriptional regulator; direct vs indirect binding not fully resolved","No structural detail on promoter occupancy"]},{"year":2020,"claim":"Demonstrated that the mitotic CPC function of CDCA8 extends to human female meiosis, where it is required for bipolar spindle assembly.","evidence":"RNAi in GV-stage human oocytes with immunofluorescence and live imaging","pmids":["32088244"],"confidence":"Medium","gaps":["Single lab","Mechanism of microtubule assembly defect not dissected","CPC partner dependence in oocytes not tested"]},{"year":2021,"claim":"Defined post-transcriptional repression of CDCA8 by miR-133b and an upstream MYBL2 activator, and linked CDCA8 to DNA-damage/RAD51 control affecting drug sensitivity.","evidence":"Dual-luciferase reporter, rescue assays, MYBL2 binding analysis, RAD51 foci and γH2AX assays","pmids":["33971546","33575078"],"confidence":"Medium","gaps":["Mechanism linking CDCA8 to RAD51 accumulation not established","miRNA effects single-lab"]},{"year":2021,"claim":"Connected CDCA8 to proliferation/survival signaling, showing knockdown induces G2/M arrest, suppresses cyclin B1/p-CDC2, and inactivates AKT/β-catenin, suppressing stem-like properties.","evidence":"shRNA knockdown, flow cytometry, RNA-seq, western blot, xenograft","pmids":["33801424"],"confidence":"Medium","gaps":["Whether signaling effects are direct or secondary to mitotic arrest unclear","E2F1 partner identified only by microarray in companion glioma work [#4]"]},{"year":2022,"claim":"Resolved a dual-arm EZH2 mechanism (H3K27me3 repression of let-7b and methylation-independent E2F1 self-activation) driving CDCA8 transcription, integrating epigenetic and transcription-factor control.","evidence":"ChIP-seq, EZH2 catalytic mutants, let-7b gain/loss-of-function, transcriptomics","pmids":["35094010"],"confidence":"High","gaps":["Generality of dual mechanism beyond prostate cancer untested at the time","Direct E2F1 occupancy of CDCA8 promoter inferred"]},{"year":2022,"claim":"Revealed a non-mitotic moonlighting role: CDCA8 complexes with SNAI2 to bind the CD44 promoter and activate its transcription, acting as a co-activator.","evidence":"Co-IP, ChIP-qPCR, dual-luciferase reporter, lentiviral knockdown","pmids":["36358852"],"confidence":"Medium","gaps":["How a CPC subunit accesses chromatin as a co-activator is unexplained","Single lab"]},{"year":2022,"claim":"Placed CDK1 downstream of CDCA8 via rescue epistasis, providing a proliferation effector consistent with its cell-cycle role.","evidence":"shRNA knockdown with CDK1 overexpression rescue and xenograft (thyroid; replicated in oral SCC [#15])","pmids":["35517403","41091302"],"confidence":"Medium","gaps":["Whether CDCA8 controls CDK1 transcriptionally or via cell-cycle position unclear","Single-lab per tumor type"]},{"year":2023,"claim":"Defined an AKT-centered signaling mechanism whereby CDCA8 displaces PTEN from AKT to stabilize HIF1α, which feeds back to activate CDCA8 transcription.","evidence":"Co-IP, PTEN displacement assay, ChIP for HIF1α, hypoxic survival assays","pmids":["37813876"],"confidence":"Medium","gaps":["Structural basis of PTEN/AKT competition unresolved","Loop generality across cancers untested"]},{"year":2023,"claim":"Added the MEK/ERK arm and a physical TMED3 partner channeling into PI3K/AKT, broadening CDCA8's signaling outputs across tumor types.","evidence":"Co-IP, RNA-seq, western blot, AKT-activator rescue, orthotopic and in vivo models","pmids":["36639822","36991473"],"confidence":"Medium","gaps":["Directness of CDCA8 action on MEK/ERK targets unclear","TMED3-CDCA8 interaction single Co-IP context"]},{"year":2023,"claim":"Demonstrated CDCA8 promoter activity in GFRA1+ undifferentiated spermatogonia, extending its expression program to early germline.","evidence":"Transgenic promoter-reporter mice with in vivo imaging and IHC co-localization","pmids":["36898512"],"confidence":"Medium","gaps":["Functional requirement of CDCA8 in spermatogonia not tested","Promoter activity may not reflect endogenous protein"]},{"year":2026,"claim":"Completed multi-tier expression control by defining USP35-mediated deubiquitination/stabilization, YTHDF3/eIF3A m6A-dependent translational enhancement, and a HAUS1-EZH2-E2F1 transcriptional axis.","evidence":"Co-IP, ubiquitination IP, CHX chase, m6A mapping, YTHDF3/eIF3A Co-IP, ChIP, spindle assays","pmids":["42002994","41565643","41546483"],"confidence":"Medium","gaps":["Coordination between transcriptional, translational, and stability layers in vivo not integrated","Single study per mechanism"]},{"year":null,"claim":"How CDCA8's structural CPC function mechanistically intersects with its transcriptional co-activator and AKT/HIF1α signaling roles, and whether these are separable activities, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking CPC and chromatin co-activator functions","Causal ordering of mitotic arrest vs signaling changes upon knockdown not disentangled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,5,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,14]}],"complexes":["Chromosomal Passenger Complex (CPC)"],"partners":["INCENP","SNAI2","TMED3","USP35","EZH2","YTHDF3","YBX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q53HL2","full_name":"Borealin","aliases":["Cell division cycle-associated protein 8","Dasra-B","hDasra-B","Pluripotent embryonic stem cell-related gene 3 protein"],"length_aa":280,"mass_kda":31.3,"function":"Component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Major effector of the TTK kinase in the control of attachment-error-correction and chromosome alignment","subcellular_location":"Nucleus, nucleolus; Cytoplasm; Cytoplasm, cytoskeleton, spindle; Chromosome, centromere","url":"https://www.uniprot.org/uniprotkb/Q53HL2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CDCA8","classification":"Common Essential","n_dependent_lines":1203,"n_total_lines":1208,"dependency_fraction":0.9958609271523179},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"AURKB","stoichiometry":0.2},{"gene":"EEF1G","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"NUCKS1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CDCA8","total_profiled":1310},"omim":[{"mim_id":"620959","title":"UBIQUITIN-SPECIFIC PEPTIDASE 35; USP35","url":"https://www.omim.org/entry/620959"},{"mim_id":"617224","title":"GROWTH ARREST-SPECIFIC 2-LIKE 3; GAS2L3","url":"https://www.omim.org/entry/617224"},{"mim_id":"609977","title":"CELL DIVISION CYCLE-ASSOCIATED PROTEIN 8; CDCA8","url":"https://www.omim.org/entry/609977"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":31.6},{"tissue":"lymphoid tissue","ntpm":36.1},{"tissue":"testis","ntpm":21.6}],"url":"https://www.proteinatlas.org/search/CDCA8"},"hgnc":{"alias_symbol":["FLJ12042","MESRGP","BOR","DasraB"],"prev_symbol":[]},"alphafold":{"accession":"Q53HL2","domains":[{"cath_id":"-","chopping":"207-217_226-280","consensus_level":"medium","plddt":80.6483,"start":207,"end":280}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53HL2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53HL2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53HL2-F1-predicted_aligned_error_v6.png","plddt_mean":67.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDCA8","jax_strain_url":"https://www.jax.org/strain/search?query=CDCA8"},"sequence":{"accession":"Q53HL2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53HL2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53HL2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53HL2"}},"corpus_meta":[{"pmid":"29467944","id":"PMC_29467944","title":"Distinct expression of CDCA3, CDCA5, and CDCA8 leads to shorter relapse free survival in breast cancer patient.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29467944","citation_count":76,"is_preprint":false},{"pmid":"26170459","id":"PMC_26170459","title":"Transcriptional activation of human CDCA8 gene regulated by transcription factor NF-Y in embryonic stem cells and cancer cells.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26170459","citation_count":60,"is_preprint":false},{"pmid":"33801424","id":"PMC_33801424","title":"Silencing CDCA8 Suppresses Hepatocellular Carcinoma Growth and Stemness via Restoration of ATF3 Tumor Suppressor and Inactivation of AKT/β-Catenin Signaling.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33801424","citation_count":49,"is_preprint":false},{"pmid":"30953709","id":"PMC_30953709","title":"CDCA8 is a key mediator of estrogen-stimulated cell proliferation in breast cancer cells.","date":"2019","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30953709","citation_count":39,"is_preprint":false},{"pmid":"30142792","id":"PMC_30142792","title":"CDCA8 expression and its clinical relevance in patients with bladder cancer.","date":"2018","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30142792","citation_count":38,"is_preprint":false},{"pmid":"33575078","id":"PMC_33575078","title":"CDCA8, targeted by MYBL2, promotes malignant progression and olaparib insensitivity in ovarian cancer.","date":"2021","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33575078","citation_count":34,"is_preprint":false},{"pmid":"25866227","id":"PMC_25866227","title":"Expression of CDCA8 correlates closely with FOXM1 in breast cancer: public microarray data analysis and immunohistochemical study.","date":"2015","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/25866227","citation_count":31,"is_preprint":false},{"pmid":"36639822","id":"PMC_36639822","title":"CDCA8 induced by NF-YA promotes hepatocellular carcinoma progression by regulating the MEK/ERK pathway.","date":"2023","source":"Experimental hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36639822","citation_count":30,"is_preprint":false},{"pmid":"31875977","id":"PMC_31875977","title":"KIF18B promotes the proliferation of pancreatic ductal adenocarcinoma via activating the expression of CDCA8.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31875977","citation_count":29,"is_preprint":false},{"pmid":"18337066","id":"PMC_18337066","title":"Loss of Borealin/DasraB leads to defective cell proliferation, p53 accumulation and early embryonic lethality.","date":"2008","source":"Mechanisms of 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proliferation, migration, and invasion of lung adenocarcinoma by targeting CDCA8.","date":"2021","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/33971546","citation_count":22,"is_preprint":false},{"pmid":"32088244","id":"PMC_32088244","title":"CDCA8 regulates meiotic spindle assembly and chromosome segregation during human oocyte meiosis.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/32088244","citation_count":20,"is_preprint":false},{"pmid":"33153400","id":"PMC_33153400","title":"Identification of CDCA8, DSN1 and BIRC5 in Regulating Cell Cycle and Apoptosis in Osteosarcoma Using Bioinformatics and Cell Biology.","date":"2020","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/33153400","citation_count":17,"is_preprint":false},{"pmid":"35517403","id":"PMC_35517403","title":"CDCA8 Contributes to the Development and Progression of Thyroid Cancer through Regulating CDK1.","date":"2022","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35517403","citation_count":14,"is_preprint":false},{"pmid":"34117764","id":"PMC_34117764","title":"MiR-133a-3p inhibits the malignant progression of oesophageal cancer by targeting CDCA8.","date":"2022","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34117764","citation_count":14,"is_preprint":false},{"pmid":"37813876","id":"PMC_37813876","title":"CDCA8 promotes bladder cancer survival by stabilizing HIF1α expression under hypoxia.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37813876","citation_count":11,"is_preprint":false},{"pmid":"36991473","id":"PMC_36991473","title":"TMED3 promotes the development of malignant melanoma by targeting CDCA8 and regulating PI3K/Akt pathway.","date":"2023","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/36991473","citation_count":9,"is_preprint":false},{"pmid":"36358852","id":"PMC_36358852","title":"CDCA8/SNAI2 Complex Activates CD44 to Promote Proliferation and Invasion of Pancreatic Ductal Adenocarcinoma.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36358852","citation_count":9,"is_preprint":false},{"pmid":"36085568","id":"PMC_36085568","title":"Upregulation of KIF18B facilitates malignant phenotype of esophageal squamous cell carcinoma by activating CDCA8/mTORC1 pathway.","date":"2022","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/36085568","citation_count":9,"is_preprint":false},{"pmid":"36737507","id":"PMC_36737507","title":"Let-7c-5p down-regulates immune-related CDCA8 to inhibit hepatocellular carcinoma.","date":"2023","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/36737507","citation_count":6,"is_preprint":false},{"pmid":"37853361","id":"PMC_37853361","title":"BUB1, BUB1B, CCNA2, and CDCA8, along with miR-524-5p, as clinically relevant biomarkers for the diagnosis and treatment of endometrial carcinoma.","date":"2023","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37853361","citation_count":5,"is_preprint":false},{"pmid":"37964961","id":"PMC_37964961","title":"Borealin/CDCA8 deficiency alters thyroid development and results in papillary tumor-like structures.","date":"2023","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/37964961","citation_count":4,"is_preprint":false},{"pmid":"40056827","id":"PMC_40056827","title":"CDCA8 and its multifaceted role in tumorigenesis.","date":"2025","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/40056827","citation_count":2,"is_preprint":false},{"pmid":"39823004","id":"PMC_39823004","title":"MiR-490-3p promotes cell apoptosis and cell-cycle arrest in osteosarcoma via the modulation of CDCA8/ATF3 by targeting NUSAP1.","date":"2024","source":"Translational pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/39823004","citation_count":2,"is_preprint":false},{"pmid":"41674779","id":"PMC_41674779","title":"TMEM106C, BSG, COPE, CDCA8, KPNA2, LIG1, UQCRH, and CCT5: Predictive of Survival and Immunotherapy Resistance in Hepatocellular Carcinoma.","date":"2026","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/41674779","citation_count":1,"is_preprint":false},{"pmid":"36898512","id":"PMC_36898512","title":"A 1-kb human CDCA8 promoter directs the spermatogonia-specific luciferase expression in adult testis.","date":"2023","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/36898512","citation_count":1,"is_preprint":false},{"pmid":"41091302","id":"PMC_41091302","title":"Suppressing CDCA8/CDK1 improves oral squamous cell carcinoma by modulating proliferation, apoptosis, cell cycle and migration.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41091302","citation_count":1,"is_preprint":false},{"pmid":"41565643","id":"PMC_41565643","title":"INCENP and CDCA8 predict neoadjuvant chemotherapy response and outcomes in esophageal squamous cell carcinoma.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41565643","citation_count":0,"is_preprint":false},{"pmid":"38961953","id":"PMC_38961953","title":"The correlation between the MYBL2/CDCA8 signaling pathway of malignant melanoma.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38961953","citation_count":0,"is_preprint":false},{"pmid":"41546483","id":"PMC_41546483","title":"HAUS1 Promotes Colorectal Cancer Progression by Activating CDCA8 Transcription Through the HAUS1-EZH2-E2F1 Axis.","date":"2026","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41546483","citation_count":0,"is_preprint":false},{"pmid":"41373021","id":"PMC_41373021","title":"A core stemness-associated module reveals PLK1, NUF2, KIF23, CDCA8, TOP2A, CENPF, AURKA, and ASPM as key genes in rectal cancer.","date":"2025","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/41373021","citation_count":0,"is_preprint":false},{"pmid":"42054276","id":"PMC_42054276","title":"YBX1 promotes the stemness and metastasis of NSCLC cells by promoting CDCA8 expression.","date":"2026","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/42054276","citation_count":0,"is_preprint":false},{"pmid":"42002994","id":"PMC_42002994","title":"USP35 Acts as a Dual Stabilizer of CDCA8 and PD-L1 to Coordinate the Progression and Immune Evasion in Non-Small Cell Lung Cancer.","date":"2026","source":"Combinatorial chemistry & high throughput screening","url":"https://pubmed.ncbi.nlm.nih.gov/42002994","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21223,"output_tokens":5355,"usd":0.071997,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13732,"output_tokens":4041,"usd":0.084843,"stage2_stop_reason":"end_turn"},"total_usd":0.15684,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"Borealin/CDCA8 (DasraB) is an essential component of the chromosomal passenger complex (CPC); genetic knockout in mice causes early embryonic lethality by 5.5 dpc due to mitotic defects, microtubule disorganization, absence of CPC enrichment, and p53-independent apoptosis in blastocyst cells.\",\n      \"method\": \"Targeted gene disruption (borealin-null mice), immunofluorescence for microtubule organization and CPC localization, genetic rescue by p53 deletion\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic epistasis (p53 rescue attempted), clean KO with defined cellular phenotype, multiple orthogonal methods (histology, immunofluorescence, genetic rescue), peer-reviewed\",\n      \"pmids\": [\"18337066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Transcription factor NF-Y (via NF-YA subunit) and CREB1 directly bind cis-elements in the CDCA8 basic promoter to activate transcription; NF-Y overexpression enhances and NF-Y knockdown reduces CDCA8 transcription. The NF-YA subunit that binds the promoter is primarily a short isoform in hESCs and a long isoform in cancer cells, indicating distinct activation mechanisms.\",\n      \"method\": \"Reporter gene assays, mutation analyses of promoter cis-elements, electrophoretic mobility shift assays (EMSA), NF-Y overexpression and knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EMSA, reporter assays, mutagenesis, gain/loss-of-function), single lab but comprehensive study\",\n      \"pmids\": [\"26170459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDCA8 protein localizes dynamically from germinal vesicle breakdown (GVBD) to metaphase II in human oocytes; RNAi-mediated depletion of CDCA8 causes multipolar spindles, disordered chromosomes, and impaired microtubule assembly, with extended polar body extrusion time, establishing a role for CDCA8 in bipolar spindle formation and chromosome segregation during human oocyte meiosis.\",\n      \"method\": \"RNAi knockdown in GV-stage human oocytes, immunofluorescence for spindle and chromosome morphology, live imaging\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined spindle/chromosome phenotype, but single lab study\",\n      \"pmids\": [\"32088244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDCA8 silencing in hepatocellular carcinoma cells downregulates cyclin B1 and p-CDC2, induces G2/M arrest, increases tumor-suppressive ATF3 and GADD34 protein levels, and inactivates AKT/β-catenin signaling, suppressing cancer stem cell properties (sphere formation, CD133+ population).\",\n      \"method\": \"shRNA knockdown, flow cytometry, RNA sequencing, western blot, xenograft model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined molecular readouts (western blot, RNA-seq), in vivo xenograft validation, single lab\",\n      \"pmids\": [\"33801424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDCA8 synergizes with E2F1 to promote glioma cell proliferation and migration; gene microarray identified E2F1 as a biological partner of CDCA8.\",\n      \"method\": \"Gene microarray chip, in vitro and in vivo loss-of-function assays (proliferation, migration, apoptosis)\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, E2F1 interaction identified only by expression microarray without direct protein interaction confirmation\",\n      \"pmids\": [\"33542211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EZH2 activates CDCA8 expression in prostate cancer through two mechanisms: (1) methyltransferase-dependent H3K27 trimethylation represses let-7b miRNA, relieving let-7b-mediated suppression of CDCA8 transcripts; (2) methyltransferase-independent recruitment of E2F1 to the E2F1 own promoter drives E2F1 self-activation, which then promotes CDCA8 transcription.\",\n      \"method\": \"Genome-wide chromatin assays (ChIP-seq), let-7b overexpression/knockdown, EZH2 catalytic mutant constructs, transcriptomic profiling\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide assays plus mechanistic dissection of methyltransferase-dependent and -independent arms, multiple orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"35094010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KIF18B binds to the promoter region of CDCA8 and transcriptionally activates CDCA8 expression in pancreatic ductal adenocarcinoma cells.\",\n      \"method\": \"ChIP assay (KIF18B binding to CDCA8 promoter), qRT-PCR, KIF18B knockdown\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP evidence for promoter binding, supported by knockdown phenotype, single lab\",\n      \"pmids\": [\"31875977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDCA8 forms a complex with SNAI2 (SLUG) transcription factor; the CDCA8/SNAI2 complex binds the CD44 promoter and activates CD44 transcription, promoting proliferation and invasion of pancreatic ductal adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), ChIP-qPCR (CDCA8/SNAI2 binding to CD44 promoter), dual-luciferase reporter assay, lentiviral knockdown\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ChIP-qPCR and reporter assay in single lab; multiple orthogonal methods\",\n      \"pmids\": [\"36358852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDCA8 stabilizes HIF1α in bladder cancer by competing with PTEN for AKT binding, displacing PTEN and activating the AKT/GSK3β signaling cascade that increases HIF1α protein stability. HIF1α in turn binds the CDCA8 promoter for transcriptional activation, forming a positive-feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, western blot, PTEN displacement assay, ChIP for HIF1α at CDCA8 promoter, hypoxic cell survival assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for protein interactions plus ChIP for promoter binding, mechanistic loop proposed with supporting experiments, single lab\",\n      \"pmids\": [\"37813876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NF-YA transcription factor upregulates CDCA8 expression in hepatocellular carcinoma, and CDCA8 knockdown suppresses the MEK/ERK pathway and inhibits expression of downstream targets TPM3, NECAP2, and USP13; CDCA8 knockdown attenuates NF-YA-mediated cell invasion.\",\n      \"method\": \"RNA sequencing, next-generation sequencing, qRT-PCR, western blot, NF-YA overexpression, orthotopic tumor model\",\n      \"journal\": \"Experimental hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus western blot validation and in vivo model, single lab\",\n      \"pmids\": [\"36639822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDCA8 knockdown in thyroid cancer cells reduces CDK1 levels, and CDK1 overexpression partially rescues the tumor-suppressive effects of CDCA8 knockdown, placing CDK1 downstream of CDCA8 in thyroid cancer progression.\",\n      \"method\": \"shRNA knockdown, CDK1 overexpression rescue, in vitro proliferation/apoptosis assays, in vivo xenograft\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by rescue experiment, supported by in vivo data, single lab\",\n      \"pmids\": [\"35517403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-133b directly targets CDCA8 mRNA (validated by dual-luciferase reporter assay); miR-133b overexpression reduces CDCA8 protein and inhibits proliferation, invasion, and migration of lung adenocarcinoma cells, which is reversed by CDCA8 overexpression.\",\n      \"method\": \"Dual-luciferase reporter assay, qRT-PCR, western blot, CCK-8, scratch healing, Transwell assays\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct miRNA-target validation by luciferase reporter plus rescue experiment, single lab\",\n      \"pmids\": [\"33971546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-133a-3p directly targets the 3'UTR of CDCA8 mRNA (validated by dual-luciferase reporter assay); miR-133a-3p overexpression reduces CDCA8 expression and suppresses proliferation, migration, and invasion of esophageal cancer cells, reversible by CDCA8 restoration.\",\n      \"method\": \"Dual-luciferase reporter assay, qRT-PCR, western blot, CCK-8, flow cytometry, Transwell assays\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter for direct targeting plus rescue functional experiments, single lab\",\n      \"pmids\": [\"34117764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Let-7c-5p directly targets and negatively regulates CDCA8 mRNA (validated by dual-luciferase reporter and western blot); CDCA8 overexpression reverses the tumor-suppressive effects of let-7c-5p on HCC cells.\",\n      \"method\": \"Dual-luciferase reporter assay, western blot, CCK-8, Transwell, wound healing, flow cytometry, rescue experiment\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation by luciferase reporter plus functional rescue, single lab\",\n      \"pmids\": [\"36737507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMED3 physically interacts with CDCA8 (co-immunoprecipitation); CDCA8 mediates the oncogenic effects of TMED3 in malignant melanoma by activating PI3K/AKT signaling; CDCA8 overexpression rescues the inhibitory effects of TMED3 knockdown, and CDCA8 knockdown suppresses P-AKT and P-PI3K levels.\",\n      \"method\": \"Co-immunoprecipitation, western blot, siRNA knockdown, SC79 (AKT activator) rescue, in vitro and in vivo assays\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for interaction plus epistasis by rescue experiments, single lab\",\n      \"pmids\": [\"36991473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDCA8 knockdown in oral squamous cell carcinoma reduces CDK1 and CDK2 levels; CDK1 inhibitor RO3306 phenocopies CDCA8 knockdown, and CDK1 overexpression reverses the growth-suppressive effect of CDCA8 knockdown, establishing CDK1 as a downstream effector of CDCA8.\",\n      \"method\": \"shRNA knockdown, CDK1 inhibitor (RO3306), CDK1 overexpression rescue, KEGG pathway analysis, in vivo xenograft\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic/pharmacological epistasis with rescue, in vivo confirmation, single lab\",\n      \"pmids\": [\"41091302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP35 deubiquitinase directly interacts with CDCA8 (validated by Co-IP) and removes ubiquitin chains from CDCA8, stabilizing the protein and preventing proteasomal degradation; USP35 knockdown reduces CDCA8 protein levels and inhibits NSCLC cell proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, IP-western blot for ubiquitination, cycloheximide chase assay, siRNA knockdown\",\n      \"journal\": \"Combinatorial chemistry & high throughput screening\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction plus ubiquitination IP and protein stability assay, single lab\",\n      \"pmids\": [\"42002994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"HAUS1 physically interacts with EZH2 and facilitates recruitment of E2F1 to the CDCA8 promoter via a methylation-independent HAUS1-EZH2-E2F1 axis, thereby transcriptionally activating CDCA8; CDCA8 loss abrogates oncogenic effects of HAUS1 overexpression in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation (HAUS1-EZH2), ChIP for E2F1 at CDCA8 promoter, transcriptomic profiling, CDCA8 rescue/knockdown epistasis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus transcriptomic profiling plus genetic epistasis, single lab\",\n      \"pmids\": [\"41546483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The 5'UTR of INCENP and 3'UTR of CDCA8 undergo m6A methylation (at specific GGACT motifs); YTHDF3 recognizes these m6A sites and facilitates translation of INCENP and CDCA8 through interaction with eIF3A; inhibition of INCENP and CDCA8 enhances chemotherapy sensitivity by promoting multipolar spindle formation.\",\n      \"method\": \"m6A sequencing/mapping, YTHDF3 binding assays, eIF3A interaction (Co-IP), multipolar spindle formation assay, functional chemosensitivity experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A mapping at defined positions plus YTHDF3/eIF3A co-IP and functional spindle assay, single study\",\n      \"pmids\": [\"41565643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YBX1 directly binds CDCA8 mRNA and positively regulates CDCA8 expression; YBX1 overexpression promotes NSCLC cancer stem cell properties (SOX/NANOG expression, sphere formation, migration/invasion), and these effects are reversed by CDCA8 knockdown.\",\n      \"method\": \"RNA immunoprecipitation or binding assay (YBX1-CDCA8 mRNA), western blot, qRT-PCR, sphere-formation assay, Transwell, xenograft rescue\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, binding method not fully detailed in abstract, functional rescue provided\",\n      \"pmids\": [\"42054276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The 1-kb human CDCA8 promoter drives specific expression in GFRA1+ undifferentiated spermatogonia of adult mouse testis, as demonstrated in transgenic reporter mice, indicating that CDCA8 transcription is activated in early undifferentiated spermatogonia.\",\n      \"method\": \"Transgenic mouse luciferase reporter driven by 1-kb CDCA8 promoter, in vivo imaging, immunohistochemistry/immunofluorescence for luciferase co-localization with GFRA1\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic reporter mouse with direct imaging and IHC co-localization, clean experimental design, single lab\",\n      \"pmids\": [\"36898512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYBL2 is identified as an upstream transcription factor that positively regulates CDCA8 expression in ovarian cancer; silencing of CDCA8 sensitizes ovarian cancer cells to olaparib and cisplatin by inducing G2/M arrest, increasing DNA damage, and interfering with RAD51 accumulation.\",\n      \"method\": \"Transcription factor binding analysis, CDCA8 knockdown, flow cytometry (G2/M arrest), DNA damage assays (γH2AX), RAD51 foci immunofluorescence, drug sensitivity assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular assays with defined molecular readouts (RAD51, DNA damage), MYBL2-CDCA8 regulatory link supported, single lab\",\n      \"pmids\": [\"33575078\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDCA8 (Borealin/DasraB) is an essential subunit of the Chromosomal Passenger Complex (CPC) required for bipolar spindle formation, chromosome segregation, and cytokinesis in both mitosis and meiosis; its transcription is activated by NF-Y, CREB1, MYBL2, KIF18B, and the EZH2-E2F1 axis, its mRNA is negatively regulated by miR-133b, miR-133a-3p, and let-7 family members (with m6A-YTHDF3-eIF3A-mediated translational control also described), and its protein stability is maintained by the deubiquitinase USP35; downstream, CDCA8 promotes cell proliferation and survival through CDK1, MEK/ERK, AKT/GSK3β-HIF1α, and PI3K/AKT pathways, and also acts as a transcriptional co-activator (complexing with SNAI2 to drive CD44 expression), collectively making it a multifaceted regulator whose loss causes mitotic failure, apoptosis, and embryonic lethality.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDCA8 (Borealin/DasraB) is an essential subunit of the Chromosomal Passenger Complex required for mitotic and meiotic fidelity: its loss causes microtubule disorganization, failure of CPC enrichment, p53-independent apoptosis, and early embryonic lethality in mice [#0], and its depletion in human oocytes produces multipolar spindles, disordered chromosomes, and impaired microtubule assembly during meiosis [#2]. The same spindle-organizing function underlies its requirement in cancer cells, where its expression is tightly controlled at multiple regulatory tiers. Transcriptionally, CDCA8 is activated by NF-Y/CREB1 binding to its basic promoter [#1], by the EZH2–E2F1 axis acting through both H3K27me3-dependent repression of let-7b and methyltransferase-independent E2F1 self-activation [#5, #17], and by additional upstream factors including KIF18B and MYBL2 [#6, #21]. Post-transcriptionally, CDCA8 mRNA is repressed by miR-133b, miR-133a-3p, and let-7c-5p [#11, #12, #13] and translationally enhanced through m6A modification read by YTHDF3 in concert with eIF3A [#18], while its protein is stabilized against proteasomal degradation by the deubiquitinase USP35 [#16]. Beyond its structural CPC role, CDCA8 acts as a transcriptional co-activator, forming a complex with SNAI2 (SLUG) to drive CD44 expression [#7], and drives proliferation and survival through CDK1 [#10, #15] and through AKT-axis signaling, including PTEN displacement that stabilizes HIF1\\u03b1 in a positive-feedback loop [#8]. A 1-kb CDCA8 promoter additionally drives expression in GFRA1+ undifferentiated spermatogonia, indicating activity in early germline cells [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established CDCA8/Borealin as an essential CPC component whose loss is incompatible with mitotic progression, defining its core cellular function.\",\n      \"evidence\": \"Targeted gene disruption in mice with immunofluorescence and genetic p53-deletion rescue\",\n      \"pmids\": [\"18337066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of CPC enrichment defect not resolved at structural level\", \"Does not address meiotic role\", \"p53-independence of apoptosis leaves death mechanism unexplained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the first direct transcriptional activators of CDCA8, showing NF-Y and CREB1 bind defined promoter cis-elements with isoform-specific activation in stem versus cancer cells.\",\n      \"evidence\": \"Reporter assays, promoter mutagenesis, EMSA, and NF-Y gain/loss-of-function\",\n      \"pmids\": [\"26170459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of isoform switch on downstream phenotype unclear\", \"Does not connect promoter activity to proliferation outcomes\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the transcriptional regulatory network by identifying KIF18B as a promoter-binding activator of CDCA8 in pancreatic cancer.\",\n      \"evidence\": \"ChIP, qRT-PCR, and KIF18B knockdown\",\n      \"pmids\": [\"31875977\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KIF18B is atypical as a transcriptional regulator; direct vs indirect binding not fully resolved\", \"No structural detail on promoter occupancy\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that the mitotic CPC function of CDCA8 extends to human female meiosis, where it is required for bipolar spindle assembly.\",\n      \"evidence\": \"RNAi in GV-stage human oocytes with immunofluorescence and live imaging\",\n      \"pmids\": [\"32088244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of microtubule assembly defect not dissected\", \"CPC partner dependence in oocytes not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined post-transcriptional repression of CDCA8 by miR-133b and an upstream MYBL2 activator, and linked CDCA8 to DNA-damage/RAD51 control affecting drug sensitivity.\",\n      \"evidence\": \"Dual-luciferase reporter, rescue assays, MYBL2 binding analysis, RAD51 foci and \\u03b3H2AX assays\",\n      \"pmids\": [\"33971546\", \"33575078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CDCA8 to RAD51 accumulation not established\", \"miRNA effects single-lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected CDCA8 to proliferation/survival signaling, showing knockdown induces G2/M arrest, suppresses cyclin B1/p-CDC2, and inactivates AKT/\\u03b2-catenin, suppressing stem-like properties.\",\n      \"evidence\": \"shRNA knockdown, flow cytometry, RNA-seq, western blot, xenograft\",\n      \"pmids\": [\"33801424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether signaling effects are direct or secondary to mitotic arrest unclear\", \"E2F1 partner identified only by microarray in companion glioma work [#4]\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved a dual-arm EZH2 mechanism (H3K27me3 repression of let-7b and methylation-independent E2F1 self-activation) driving CDCA8 transcription, integrating epigenetic and transcription-factor control.\",\n      \"evidence\": \"ChIP-seq, EZH2 catalytic mutants, let-7b gain/loss-of-function, transcriptomics\",\n      \"pmids\": [\"35094010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of dual mechanism beyond prostate cancer untested at the time\", \"Direct E2F1 occupancy of CDCA8 promoter inferred\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a non-mitotic moonlighting role: CDCA8 complexes with SNAI2 to bind the CD44 promoter and activate its transcription, acting as a co-activator.\",\n      \"evidence\": \"Co-IP, ChIP-qPCR, dual-luciferase reporter, lentiviral knockdown\",\n      \"pmids\": [\"36358852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a CPC subunit accesses chromatin as a co-activator is unexplained\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed CDK1 downstream of CDCA8 via rescue epistasis, providing a proliferation effector consistent with its cell-cycle role.\",\n      \"evidence\": \"shRNA knockdown with CDK1 overexpression rescue and xenograft (thyroid; replicated in oral SCC [#15])\",\n      \"pmids\": [\"35517403\", \"41091302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CDCA8 controls CDK1 transcriptionally or via cell-cycle position unclear\", \"Single-lab per tumor type\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined an AKT-centered signaling mechanism whereby CDCA8 displaces PTEN from AKT to stabilize HIF1\\u03b1, which feeds back to activate CDCA8 transcription.\",\n      \"evidence\": \"Co-IP, PTEN displacement assay, ChIP for HIF1\\u03b1, hypoxic survival assays\",\n      \"pmids\": [\"37813876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of PTEN/AKT competition unresolved\", \"Loop generality across cancers untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Added the MEK/ERK arm and a physical TMED3 partner channeling into PI3K/AKT, broadening CDCA8's signaling outputs across tumor types.\",\n      \"evidence\": \"Co-IP, RNA-seq, western blot, AKT-activator rescue, orthotopic and in vivo models\",\n      \"pmids\": [\"36639822\", \"36991473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of CDCA8 action on MEK/ERK targets unclear\", \"TMED3-CDCA8 interaction single Co-IP context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated CDCA8 promoter activity in GFRA1+ undifferentiated spermatogonia, extending its expression program to early germline.\",\n      \"evidence\": \"Transgenic promoter-reporter mice with in vivo imaging and IHC co-localization\",\n      \"pmids\": [\"36898512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional requirement of CDCA8 in spermatogonia not tested\", \"Promoter activity may not reflect endogenous protein\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Completed multi-tier expression control by defining USP35-mediated deubiquitination/stabilization, YTHDF3/eIF3A m6A-dependent translational enhancement, and a HAUS1-EZH2-E2F1 transcriptional axis.\",\n      \"evidence\": \"Co-IP, ubiquitination IP, CHX chase, m6A mapping, YTHDF3/eIF3A Co-IP, ChIP, spindle assays\",\n      \"pmids\": [\"42002994\", \"41565643\", \"41546483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Coordination between transcriptional, translational, and stability layers in vivo not integrated\", \"Single study per mechanism\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDCA8's structural CPC function mechanistically intersects with its transcriptional co-activator and AKT/HIF1\\u03b1 signaling roles, and whether these are separable activities, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking CPC and chromatin co-activator functions\", \"Causal ordering of mitotic arrest vs signaling changes upon knockdown not disentangled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 5, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 14]}\n    ],\n    \"complexes\": [\"Chromosomal Passenger Complex (CPC)\"],\n    \"partners\": [\"INCENP\", \"SNAI2\", \"TMED3\", \"USP35\", \"EZH2\", \"YTHDF3\", \"YBX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}