CDCA8

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).

1. 2008 High

   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

   PMID:18337066

   Open questions at the time

   • Molecular basis of CPC enrichment defect not resolved at structural level
   • Does not address meiotic role
   • p53-independence of apoptosis leaves death mechanism unexplained
2. 2015 High

   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

   PMID:26170459

   Open questions at the time

   • Functional consequence of isoform switch on downstream phenotype unclear
   • Does not connect promoter activity to proliferation outcomes
3. 2019 Medium

   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

   PMID:31875977

   Open questions at the time

   • KIF18B is atypical as a transcriptional regulator; direct vs indirect binding not fully resolved
   • No structural detail on promoter occupancy
4. 2020 Medium

   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

   PMID:32088244

   Open questions at the time

   • Single lab
   • Mechanism of microtubule assembly defect not dissected
   • CPC partner dependence in oocytes not tested
5. 2021 Medium

   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

   PMID:33575078 PMID:33971546

   Open questions at the time

   • Mechanism linking CDCA8 to RAD51 accumulation not established
   • miRNA effects single-lab
6. 2021 Medium

   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

   PMID:33801424

   Open questions at the time

   • Whether signaling effects are direct or secondary to mitotic arrest unclear
   • E2F1 partner identified only by microarray in companion glioma work [#4]
7. 2022 High

   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

   PMID:35094010

   Open questions at the time

   • Generality of dual mechanism beyond prostate cancer untested at the time
   • Direct E2F1 occupancy of CDCA8 promoter inferred
8. 2022 Medium

   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

   PMID:36358852

   Open questions at the time

   • How a CPC subunit accesses chromatin as a co-activator is unexplained
   • Single lab
9. 2022 Medium

   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])

   PMID:35517403 PMID:41091302

   Open questions at the time

   • Whether CDCA8 controls CDK1 transcriptionally or via cell-cycle position unclear
   • Single-lab per tumor type
10. 2023 Medium

    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

    PMID:37813876

    Open questions at the time

    • Structural basis of PTEN/AKT competition unresolved
    • Loop generality across cancers untested
11. 2023 Medium

    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

    PMID:36639822 PMID:36991473

    Open questions at the time

    • Directness of CDCA8 action on MEK/ERK targets unclear
    • TMED3-CDCA8 interaction single Co-IP context
12. 2023 Medium

    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

    PMID:36898512

    Open questions at the time

    • Functional requirement of CDCA8 in spermatogonia not tested
    • Promoter activity may not reflect endogenous protein
13. 2026 Medium

    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

    PMID:41546483 PMID:41565643 PMID:42002994

    Open questions at the time

    • Coordination between transcriptional, translational, and stability layers in vivo not integrated
    • Single study per mechanism

• 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.
• No structural model linking CPC and chromatin co-activator functions
• Causal ordering of mitotic arrest vs signaling changes upon knockdown not disentangled