{"gene":"SOX30","run_date":"2026-06-10T07:46:38","timeline":{"discoveries":[{"year":2014,"finding":"SOX30 directly binds to the CACTTTG sequence (+115 to +121) of the p53 promoter region and transcriptionally activates p53 expression, mediating tumor suppression in lung cancer cells.","method":"Chromatin immunoprecipitation (ChIP) assay, ectopic expression/knockdown with proliferation and apoptosis readouts, in vivo tumor formation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding shown by ChIP, functional rescue by p53 blockade, single lab with two orthogonal methods","pmids":["25435374"],"is_preprint":false},{"year":2017,"finding":"SOX30 is required for the post-meiotic round spermatid stage of spermatogenesis in male mice; Sox30-null males are completely sterile with arrest at step 3 spermiogenesis, aberrant acrosome and axoneme development, and formation of multinucleated symplasts, while females are fertile.","method":"Sox30 knockout mouse model, histological analysis, assessment of spermatogenic stages","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with specific phenotypic readout, replicated across multiple independent papers","pmids":["29247201"],"is_preprint":false},{"year":2018,"finding":"SOX30 inhibits tumor metastasis in lung cancer by two mechanisms: (1) directly transcriptionally repressing β-catenin expression, and (2) binding β-catenin protein via its amino-terminus to compete with TCF for β-catenin binding, with the carboxyl-terminus required for attenuating β-catenin transcriptional activity.","method":"Co-immunoprecipitation, ChIP assay, TOP/FOP flash reporter assay, domain deletion mutants, in vitro migration/invasion assays, in vivo metastasis models, Sox30 knockout mice","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping, transcriptional reporter assay, in vivo rescue, multiple orthogonal methods in one study","pmids":["29739711"],"is_preprint":false},{"year":2018,"finding":"SOX30 controls a core postmeiotic gene expression program in mouse testes, initiating as early as late meiotic cell stages; ChIP-seq shows SOX30 binds specific DNA sequences and its genomic occupancy correlates positively with expression of postmeiotic genes including Tnp1, Hils1, Ccdc54, and Tsks.","method":"Sox30 mutant mice, transcriptome analysis of stage-specific spermatogenic cells, ChIP-seq","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP-seq with genome-wide occupancy data plus transcriptome in defined cell populations, clean knockout model","pmids":["29866902"],"is_preprint":false},{"year":2018,"finding":"SOX30 transcription in mouse testes is regulated by retinoic acid and by the transcription factor MYBL1 before and during meiosis; SOX30 protein also binds the proximal promoter of its own gene and activates its own transcription (autoregulation).","method":"Sox30 knockout mice, retinoic acid treatment experiments, promoter reporter assays, ChIP","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding and autoregulation shown by ChIP and reporter assay, MYBL1 regulation inferred from knockout context, single lab","pmids":["29848638"],"is_preprint":false},{"year":2018,"finding":"SOX30 acts as a transcriptional regulator of desmosomal genes (DSP, JUP, DSC3) in lung adenocarcinoma by directly binding to the ACAAT motif in desmosomal gene promoter regions, thereby activating their transcription and inhibiting downstream Wnt and ERK signaling.","method":"ChIP assay, promoter binding analysis, miRNA knockdown of desmosomal genes, in vitro proliferation/migration/invasion assays, in vivo nude mouse model, SOX30-knockout carcinogenesis model, TOP/FOP flash reporter assay","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP, functional rescue experiments, in vivo validation, single lab","pmids":["29855376"],"is_preprint":false},{"year":2018,"finding":"miR-645 directly binds to the 3'-UTR of SOX30 and post-transcriptionally represses SOX30 expression in hepatocellular carcinoma cells; SOX30 in turn activates p53 transcription by directly binding its promoter.","method":"Luciferase 3'-UTR reporter assay, gain- and loss-of-function experiments, ChIP for p53 promoter binding","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter assay for miRNA targeting and promoter binding, single lab","pmids":["30312695"],"is_preprint":false},{"year":2019,"finding":"SOX30 hypermethylation at its promoter directly causes silencing of SOX30 expression in non-obstructive azoospermia (NOA) patient testicular tissues; re-expression of Sox30 in Sox30-null adult mice reverses pathological testicular damage, restores spermatogenesis, and produces spermatozoa capable of initiating pregnancy.","method":"Genome-wide methylation profiling, Sox30-null mouse model, adeno-associated virus-mediated re-expression in adult null mice, fertility testing, offspring analysis","journal":"Molecular therapy. Nucleic acids","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and rescue in vivo with defined fertility readout, genome-wide methylation data linking epigenetic silencing to expression, multiple orthogonal methods","pmids":["31835093"],"is_preprint":false},{"year":2019,"finding":"SOX30 is a target gene of miR-653-5p; miR-653-5p overexpression decreases SOX30 expression, and SOX30 overexpression or miR-653-5p inhibition reduces β-catenin expression and suppresses Wnt/β-catenin signaling in prostate cancer cells.","method":"Dual-luciferase reporter assay for miRNA-mRNA interaction, western blot, proliferation/invasion assays, siRNA knockdown","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter for miRNA targeting validated, functional pathway effects shown, single lab","pmids":["31889959"],"is_preprint":false},{"year":2019,"finding":"Dmrt1 positively regulates transcription of the Sox30 gene in Nile tilapia by directly binding to a specific cis-regulatory element (CRE) within the Sox30 promoter.","method":"Dual-luciferase reporter assay, ChIP-PCR, electrophoretic mobility shift assay (EMSA), Dmrt1 knockdown experiments","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding shown by EMSA and ChIP-PCR, reporter assay with CRE mutation, single lab in teleost model","pmids":["31690021"],"is_preprint":false},{"year":2020,"finding":"SOX30 overexpression in acute myeloid leukemia cells markedly decreases β-catenin expression, leading to inactivation of the Wnt/β-catenin pathway; restoration of β-catenin partially reverses SOX30-mediated tumor suppression, placing SOX30 upstream of β-catenin in this pathway.","method":"SOX30 overexpression/siRNA knockdown, western blot for β-catenin, β-catenin rescue experiments, xenograft mouse model","journal":"Molecular and cellular probes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by rescue experiment, in vivo xenograft, single lab","pmids":["32334007"],"is_preprint":false},{"year":2021,"finding":"Sox30 in Nile tilapia localizes to spermatocytes and spermatids in the testis and directly regulates transcription of spermiogenesis-related genes ift140 and ptprb by binding to their promoters; CRISPR/Cas9-mediated sox30 mutation causes abnormal spermiogenesis, reduced sperm motility, and male subfertility.","method":"CRISPR/Cas9 knockout, ChIP-seq, ChIP-PCR, luciferase reporter assay, comparative transcriptome analysis","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and luciferase reporter for direct target gene activation, clean genetic knockout with phenotype, single lab in teleost model","pmids":["34801758"],"is_preprint":false},{"year":2025,"finding":"SOX30 directly binds to SYCE1 and SYCE2 promoters to activate their transcription, regulating synaptonemal complex (SC) assembly; Sox30 knockout mice show defects in SC central element distribution (SYCE1, SYCE2, TEX12), impaired DNA double-strand break repair, persistence of RAD51 and RPA2 in late spermatocytes, and reduced crossover formation.","method":"Sox30-knockout mice, chromosome spreading, ChIP for SYCE1/SYCE2 promoters, immunofluorescence for SC components and recombination proteins, transcriptome co-expression analysis, Sox30 re-expression rescue","journal":"Cell proliferation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct promoter binding by ChIP, multiple SC and HR marker readouts, in vivo rescue by SOX30 re-expression, multiple orthogonal methods","pmids":["41467312"],"is_preprint":false},{"year":2026,"finding":"A human SOX30 stop-gained mutation (Arg478*) produces a C-terminal truncated protein with dramatically reduced association with HDAC3; missense mutations in the HMG domain reduce SOX30 DNA-binding ability; a P353S missense mutation modeled in mice (P382S knock-in) causes defects in late spermatocyte stages and reduces mature sperm without complete sterility.","method":"Genetic screening of NOA patients, in vitro functional assays for protein-protein interaction with HDAC3, DNA-binding assays, Sox30P382S knock-in mouse model","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional validation of mutations, knock-in mouse model with defined phenotype, single lab","pmids":["41269228"],"is_preprint":false},{"year":2026,"finding":"PFOS exposure suppresses SOX30 expression in spermatocytes, leading to downregulation of its downstream targets RPA2 and RAD51 (key homologous recombination repair proteins), resulting in unrepaired DNA double-strand breaks and spermatocyte apoptosis; overexpression of SOX30 in PFOS-exposed GC2 cells restores RPA2/RAD51 expression and rescues DSB repair capacity.","method":"In vitro PFOS treatment of GC2 spermatocyte cells, SOX30 overexpression rescue, western blot for RPA2/RAD51, chromosome spreading with high-resolution microscopy","journal":"Ecotoxicology and environmental safety","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular readouts, mechanistic rescue in cell line, single lab","pmids":["41905031"],"is_preprint":false},{"year":2026,"finding":"SOX30 suppresses ovarian cancer cell proliferation primarily through an autophagy-mediated mechanism rather than apoptosis; SOX30 overexpression induces marked autophagy and co-expression analysis links SOX30 to key autophagy-related genes.","method":"MTS assay, colony formation assay, flow cytometry, western blotting, confocal microscopy for autophagy, xenograft model, co-expression analysis","journal":"Discover oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with autophagy mechanistic readout, in vivo xenograft, single lab","pmids":["41566108"],"is_preprint":false},{"year":2014,"finding":"SOX30 expression in mouse testis is regulated by DNA methylation status at its CpG island promoter; Sox30 is hypo-methylated in testis (where it is expressed) and hypermethylated in other tissues (where it is silenced); demethylation with 5-aza-dC restores Sox30 expression in GC2, TM3, and TM4 cell lines.","method":"Methylation-specific PCR, bisulfite sequencing, 5-aza-dC demethylation treatment, RT-PCR expression analysis across tissues","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological demethylation rescue confirms epigenetic regulation, multiple tissue comparisons, single lab","pmids":["24810894"],"is_preprint":false}],"current_model":"SOX30 is a testis-enriched transcription factor (containing an HMG-box DNA-binding domain) that is essential for spermatogenesis: it binds specific promoter sequences to directly activate postmeiotic haploid gene programs (including synaptonemal complex genes SYCE1/SYCE2 and spermatid-specific genes), regulates its own transcription, associates with HDAC3 via its C-terminus, and in somatic cancer contexts acts as a tumor suppressor by directly activating p53 transcription and suppressing Wnt/β-catenin signaling through both transcriptional repression of β-catenin and protein-level competition with TCF for β-catenin binding."},"narrative":{"mechanistic_narrative":"SOX30 is an HMG-box transcription factor that functions as a master regulator of postmeiotic spermatogenesis and, in somatic tissues, as a tumor suppressor [PMID:29247201, PMID:29866902, PMID:29739711]. In the testis, SOX30 is essential for the transition through round spermatid differentiation: Sox30-null males are completely sterile, arresting at step 3 spermiogenesis with aberrant acrosome and axoneme development and multinucleated symplasts, while females are unaffected [PMID:29247201]. SOX30 establishes a core postmeiotic gene program beginning in late meiosis, binding specific DNA sequences genome-wide to drive expression of spermatid genes such as Tnp1, Hils1, Ccdc54 and Tsks [PMID:29866902], and it directly activates the synaptonemal complex genes SYCE1 and SYCE2 to support central-element assembly, DNA double-strand break repair and crossover formation [PMID:41467312]. SOX30 expression is itself controlled at multiple levels: it is restricted to testis by CpG-island promoter methylation [PMID:24810894], induced by retinoic acid and MYBL1, and reinforced by direct autoregulation of its own promoter [PMID:29848638]. Promoter hypermethylation silences SOX30 in non-obstructive azoospermia, and adeno-associated-virus re-expression of Sox30 in null adult mice restores spermatogenesis and fertility, establishing a causal link to male infertility [PMID:31835093]; a human stop-gained mutation (Arg478*) abolishes association with HDAC3 and HMG-domain missense mutations impair DNA binding [PMID:41269228]. In cancer, SOX30 acts as a tumor suppressor through two principal axes: it directly binds and transactivates the p53 promoter [PMID:25435374], and it antagonizes Wnt/β-catenin signaling both by transcriptionally repressing β-catenin and by binding β-catenin protein through its amino-terminus to compete with TCF [PMID:29739711]. SOX30 is post-transcriptionally repressed by microRNAs including miR-645 and miR-653-5p in hepatocellular, prostate and other cancers [PMID:30312695, PMID:31889959].","teleology":[{"year":2014,"claim":"Established that SOX30 tissue-restricted expression is set epigenetically, explaining why this factor is testis-specific.","evidence":"Methylation-specific PCR, bisulfite sequencing and 5-aza-dC demethylation rescue across mouse tissues and cell lines","pmids":["24810894"],"confidence":"Medium","gaps":["Does not identify the demethylating machinery in testis","Does not link methylation state to a downstream transcriptional program"]},{"year":2014,"claim":"Defined SOX30 as a direct transcriptional activator of p53, providing the first molecular mechanism for its tumor-suppressor activity.","evidence":"ChIP at the p53 promoter, ectopic expression/knockdown with proliferation and apoptosis readouts, and in vivo tumor formation in lung cancer cells","pmids":["25435374"],"confidence":"Medium","gaps":["Single lung-cancer context","Does not address whether tumor suppression requires p53 in all cell types"]},{"year":2017,"claim":"Demonstrated by clean knockout that SOX30 is absolutely required for the round spermatid stage, defining its essential developmental role.","evidence":"Sox30 knockout mouse with histological staging of spermatogenesis","pmids":["29247201"],"confidence":"High","gaps":["Did not identify direct target genes at this stage","Mechanism of symplast formation unresolved"]},{"year":2018,"claim":"Resolved the genome-wide targets of SOX30, showing it directly drives a defined postmeiotic gene program initiated in late meiosis.","evidence":"ChIP-seq plus stage-specific transcriptomics in Sox30 mutant mouse spermatogenic cells","pmids":["29866902"],"confidence":"High","gaps":["Co-factors directing SOX30 occupancy not defined","Consensus binding motif vs. cancer ACAAT/CACTTTG motifs not reconciled"]},{"year":2018,"claim":"Showed SOX30 antagonizes Wnt/β-catenin signaling through dual transcriptional and protein-level mechanisms, mapping the responsible domains.","evidence":"Reciprocal Co-IP, ChIP, TOP/FOP reporter, domain-deletion mutants, and in vivo metastasis/knockout models in lung cancer","pmids":["29739711"],"confidence":"High","gaps":["Structural basis of β-catenin/TCF competition not determined","Relative contribution of repression vs. sequestration in vivo unquantified"]},{"year":2018,"claim":"Established autoregulation and upstream control of SOX30 transcription, embedding it in the retinoic acid/MYBL1 meiotic entry circuit.","evidence":"Promoter reporter assays, ChIP for self-binding, and retinoic acid treatment in Sox30 knockout mice","pmids":["29848638"],"confidence":"Medium","gaps":["MYBL1 regulation inferred from knockout context rather than direct binding","Quantitative role of autoregulation in expression timing unclear"]},{"year":2018,"claim":"Extended SOX30 tumor suppression to direct activation of desmosomal genes, linking it to cell-adhesion control of Wnt and ERK signaling.","evidence":"ChIP at the ACAAT motif of DSP/JUP/DSC3 promoters, functional assays, and SOX30-knockout carcinogenesis model in lung adenocarcinoma","pmids":["29855376"],"confidence":"Medium","gaps":["Single lab","Mechanistic link between desmosomal genes and signaling not fully dissected"]},{"year":2018,"claim":"Identified miR-645 as an upstream repressor of SOX30, extending its p53-activating tumor-suppressor axis to hepatocellular carcinoma.","evidence":"Luciferase 3'-UTR reporter, gain/loss-of-function, and ChIP for p53 promoter binding","pmids":["30312695"],"confidence":"Medium","gaps":["Single context","Does not establish in vivo relevance of the miRNA axis"]},{"year":2019,"claim":"Provided causal in vivo proof that SOX30 silencing underlies human azoospermia and that restoring it rescues fertility.","evidence":"Genome-wide methylation profiling of NOA testes plus AAV-mediated Sox30 re-expression in null adult mice with offspring analysis","pmids":["31835093"],"confidence":"High","gaps":["Frequency of SOX30 methylation across NOA cohorts not established","Therapeutic translatability untested in human tissue"]},{"year":2019,"claim":"Confirmed conserved transcriptional control of SOX30 in spermatogenesis by Dmrt1 in a teleost, and added miR-653-5p as another repressor in cancer.","evidence":"EMSA/ChIP-PCR/reporter for Dmrt1 binding in Nile tilapia; dual-luciferase and functional assays for miR-653-5p in prostate cancer","pmids":["31690021","31889959"],"confidence":"Medium","gaps":["Cross-species conservation of Dmrt1 regulation in mammals untested","miR-653-5p axis shown in single cell context"]},{"year":2020,"claim":"Placed SOX30 genetically upstream of β-catenin in leukemia, generalizing its Wnt-suppressor role beyond solid tumors.","evidence":"Overexpression/knockdown, β-catenin rescue epistasis, and xenografts in acute myeloid leukemia cells","pmids":["32334007"],"confidence":"Medium","gaps":["Direct binding to β-catenin promoter in AML not shown","Single lab"]},{"year":2021,"claim":"Demonstrated conserved direct target-gene activation by Sox30 driving spermiogenesis in a teleost model.","evidence":"CRISPR/Cas9 knockout, ChIP-seq/ChIP-PCR and reporter assays for ift140 and ptprb in Nile tilapia","pmids":["34801758"],"confidence":"Medium","gaps":["Mammalian orthology of ift140/ptprb regulation untested","Subfertility vs. mouse sterility difference unexplained"]},{"year":2025,"claim":"Revealed an earlier meiotic role for SOX30 in synaptonemal complex assembly and recombination, predating its postmeiotic function.","evidence":"Sox30-knockout chromosome spreads, ChIP at SYCE1/SYCE2 promoters, immunofluorescence for SC/recombination markers and re-expression rescue","pmids":["41467312"],"confidence":"High","gaps":["How SOX30 coordinates meiotic and postmeiotic programs unclear","Direct vs. indirect effect on RAD51/RPA2 persistence not fully separated"]},{"year":2026,"claim":"Connected human SOX30 coding mutations to infertility and mapped the functional consequences of HMG-domain and C-terminal lesions.","evidence":"NOA patient genetic screening, in vitro HDAC3-interaction and DNA-binding assays, and a Sox30 P382S knock-in mouse","pmids":["41269228"],"confidence":"Medium","gaps":["Functional role of the SOX30–HDAC3 interaction in vivo undefined","Genotype–phenotype correlation in larger cohorts lacking"]},{"year":2026,"claim":"Identified SOX30 as a node linking environmental toxicant exposure to homologous-recombination repair failure in spermatocytes.","evidence":"PFOS treatment of GC2 cells with SOX30 overexpression rescue and RPA2/RAD51 readouts plus chromosome spreading","pmids":["41905031"],"confidence":"Medium","gaps":["In vivo PFOS-SOX30 axis not tested","Mechanism of PFOS-induced SOX30 suppression unknown"]},{"year":2026,"claim":"Extended SOX30 tumor suppression to an autophagy-dependent rather than apoptotic mechanism in ovarian cancer.","evidence":"Proliferation/colony/flow assays, autophagy confocal imaging, co-expression analysis and xenografts","pmids":["41566108"],"confidence":"Medium","gaps":["Direct autophagy gene targets not identified","Relationship to p53/Wnt axes unresolved"]},{"year":null,"claim":"How SOX30 partitions between its meiotic, postmeiotic and somatic tumor-suppressor programs through context-specific cofactors and binding motifs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of SOX30 on DNA or with β-catenin/HDAC3","Cofactors directing tissue-specific occupancy unknown","Reconciliation of distinct binding motifs (CACTTTG, ACAAT, SC promoters) lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,3,5,12]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,3,13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[1,3,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2,7]}],"complexes":[],"partners":["CTNNB1","HDAC3","TCF"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94993","full_name":"Transcription factor SOX-30","aliases":[],"length_aa":753,"mass_kda":81.9,"function":"Acts both as a transcriptional activator and a repressor (PubMed:10359848, PubMed:29739711). Binds to the DNA sequence 5'-ACAAT-3' and shows a preference for guanine residues surrounding this core motif (PubMed:10359848). Binds to its own promoter and activates its own transcription (By similarity). Required to activate the expression of postmeiotic genes involved in spermiogenesis (By similarity). Binds to the promoter region of CTNNB1 and represses its transcription which leads to inhibition of Wnt signaling (PubMed:29739711). Also inhibits Wnt signaling by binding to the CTNNB1 protein, preventing interaction of CTNNB1 with TCF7L2/TCF4 (PubMed:29739711)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O94993/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SOX30","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SOX30","total_profiled":1310},"omim":[{"mim_id":"606698","title":"SRY-BOX 30; SOX30","url":"https://www.omim.org/entry/606698"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":76.2}],"url":"https://www.proteinatlas.org/search/SOX30"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O94993","domains":[{"cath_id":"1.10.30.10","chopping":"312-399","consensus_level":"high","plddt":88.9106,"start":312,"end":399}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94993","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94993-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94993-F1-predicted_aligned_error_v6.png","plddt_mean":49.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SOX30","jax_strain_url":"https://www.jax.org/strain/search?query=SOX30"},"sequence":{"accession":"O94993","fasta_url":"https://rest.uniprot.org/uniprotkb/O94993.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94993/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94993"}},"corpus_meta":[{"pmid":"25435374","id":"PMC_25435374","title":"SOX30, a novel epigenetic silenced tumor suppressor, promotes tumor cell apoptosis by transcriptional activating p53 in lung cancer.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/25435374","citation_count":64,"is_preprint":false},{"pmid":"29247201","id":"PMC_29247201","title":"SOX30 is required for male fertility in mice.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29247201","citation_count":55,"is_preprint":false},{"pmid":"29739711","id":"PMC_29739711","title":"SOX30 Inhibits Tumor Metastasis through Attenuating Wnt-Signaling via Transcriptional and Posttranslational Regulation of β-Catenin in Lung Cancer.","date":"2018","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/29739711","citation_count":52,"is_preprint":false},{"pmid":"29866902","id":"PMC_29866902","title":"Sox30 initiates transcription of haploid genes during late meiosis and spermiogenesis in mouse testes.","date":"2018","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29866902","citation_count":48,"is_preprint":false},{"pmid":"24810894","id":"PMC_24810894","title":"Epigenetic regulation of sox30 is associated with testis development in mice.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24810894","citation_count":45,"is_preprint":false},{"pmid":"29848638","id":"PMC_29848638","title":"The transcription factor SOX30 is a key regulator of mouse spermiogenesis.","date":"2018","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29848638","citation_count":43,"is_preprint":false},{"pmid":"21143990","id":"PMC_21143990","title":"Characterization, phylogeny, alternative splicing and expression of Sox30 gene.","date":"2010","source":"BMC molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21143990","citation_count":42,"is_preprint":false},{"pmid":"31889959","id":"PMC_31889959","title":"SOX30, a target gene of miR-653-5p, represses the proliferation and invasion of prostate cancer cells through inhibition of Wnt/β-catenin signaling.","date":"2019","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31889959","citation_count":30,"is_preprint":false},{"pmid":"31835093","id":"PMC_31835093","title":"Epigenetic Inactivation of SOX30 Is Associated with Male Infertility and Offers a Therapy Target for Non-obstructive Azoospermia.","date":"2019","source":"Molecular therapy. 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Synaptonemal Complex Assembly and Homologous Recombination in Male Meiosis.","date":"2025","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/41467312","citation_count":0,"is_preprint":false},{"pmid":"41373817","id":"PMC_41373817","title":"SOX18 and SOX30 in NSCLC: The Epigenetic Landscape of Methylation, miRNA Regulation, and Network Crosstalk in Tumor Progression.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41373817","citation_count":0,"is_preprint":false},{"pmid":"41300700","id":"PMC_41300700","title":"Molecular Characterization and Expression Patterns of Sox3 and Sox30 Genes and Response to Exogenous Hormones in the Chinese Soft-Shelled Turtle (Pelodiscus sinensis).","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/41300700","citation_count":0,"is_preprint":false},{"pmid":"41269228","id":"PMC_41269228","title":"Mutations of SOX30 are identified in azoospermic human patients and 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tumor formation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding shown by ChIP, functional rescue by p53 blockade, single lab with two orthogonal methods\",\n      \"pmids\": [\"25435374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SOX30 is required for the post-meiotic round spermatid stage of spermatogenesis in male mice; Sox30-null males are completely sterile with arrest at step 3 spermiogenesis, aberrant acrosome and axoneme development, and formation of multinucleated symplasts, while females are fertile.\",\n      \"method\": \"Sox30 knockout mouse model, histological analysis, assessment of spermatogenic stages\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with specific phenotypic readout, replicated across multiple independent papers\",\n      \"pmids\": [\"29247201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SOX30 inhibits tumor metastasis in lung cancer by two mechanisms: (1) directly transcriptionally repressing β-catenin expression, and (2) binding β-catenin protein via its amino-terminus to compete with TCF for β-catenin binding, with the carboxyl-terminus required for attenuating β-catenin transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay, TOP/FOP flash reporter assay, domain deletion mutants, in vitro migration/invasion assays, in vivo metastasis models, Sox30 knockout mice\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping, transcriptional reporter assay, in vivo rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"29739711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SOX30 controls a core postmeiotic gene expression program in mouse testes, initiating as early as late meiotic cell stages; ChIP-seq shows SOX30 binds specific DNA sequences and its genomic occupancy correlates positively with expression of postmeiotic genes including Tnp1, Hils1, Ccdc54, and Tsks.\",\n      \"method\": \"Sox30 mutant mice, transcriptome analysis of stage-specific spermatogenic cells, ChIP-seq\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP-seq with genome-wide occupancy data plus transcriptome in defined cell populations, clean knockout model\",\n      \"pmids\": [\"29866902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SOX30 transcription in mouse testes is regulated by retinoic acid and by the transcription factor MYBL1 before and during meiosis; SOX30 protein also binds the proximal promoter of its own gene and activates its own transcription (autoregulation).\",\n      \"method\": \"Sox30 knockout mice, retinoic acid treatment experiments, promoter reporter assays, ChIP\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding and autoregulation shown by ChIP and reporter assay, MYBL1 regulation inferred from knockout context, single lab\",\n      \"pmids\": [\"29848638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SOX30 acts as a transcriptional regulator of desmosomal genes (DSP, JUP, DSC3) in lung adenocarcinoma by directly binding to the ACAAT motif in desmosomal gene promoter regions, thereby activating their transcription and inhibiting downstream Wnt and ERK signaling.\",\n      \"method\": \"ChIP assay, promoter binding analysis, miRNA knockdown of desmosomal genes, in vitro proliferation/migration/invasion assays, in vivo nude mouse model, SOX30-knockout carcinogenesis model, TOP/FOP flash reporter assay\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP, functional rescue experiments, in vivo validation, single lab\",\n      \"pmids\": [\"29855376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-645 directly binds to the 3'-UTR of SOX30 and post-transcriptionally represses SOX30 expression in hepatocellular carcinoma cells; SOX30 in turn activates p53 transcription by directly binding its promoter.\",\n      \"method\": \"Luciferase 3'-UTR reporter assay, gain- and loss-of-function experiments, ChIP for p53 promoter binding\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter assay for miRNA targeting and promoter binding, single lab\",\n      \"pmids\": [\"30312695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SOX30 hypermethylation at its promoter directly causes silencing of SOX30 expression in non-obstructive azoospermia (NOA) patient testicular tissues; re-expression of Sox30 in Sox30-null adult mice reverses pathological testicular damage, restores spermatogenesis, and produces spermatozoa capable of initiating pregnancy.\",\n      \"method\": \"Genome-wide methylation profiling, Sox30-null mouse model, adeno-associated virus-mediated re-expression in adult null mice, fertility testing, offspring analysis\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and rescue in vivo with defined fertility readout, genome-wide methylation data linking epigenetic silencing to expression, multiple orthogonal methods\",\n      \"pmids\": [\"31835093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SOX30 is a target gene of miR-653-5p; miR-653-5p overexpression decreases SOX30 expression, and SOX30 overexpression or miR-653-5p inhibition reduces β-catenin expression and suppresses Wnt/β-catenin signaling in prostate cancer cells.\",\n      \"method\": \"Dual-luciferase reporter assay for miRNA-mRNA interaction, western blot, proliferation/invasion assays, siRNA knockdown\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter for miRNA targeting validated, functional pathway effects shown, single lab\",\n      \"pmids\": [\"31889959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Dmrt1 positively regulates transcription of the Sox30 gene in Nile tilapia by directly binding to a specific cis-regulatory element (CRE) within the Sox30 promoter.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP-PCR, electrophoretic mobility shift assay (EMSA), Dmrt1 knockdown experiments\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding shown by EMSA and ChIP-PCR, reporter assay with CRE mutation, single lab in teleost model\",\n      \"pmids\": [\"31690021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SOX30 overexpression in acute myeloid leukemia cells markedly decreases β-catenin expression, leading to inactivation of the Wnt/β-catenin pathway; restoration of β-catenin partially reverses SOX30-mediated tumor suppression, placing SOX30 upstream of β-catenin in this pathway.\",\n      \"method\": \"SOX30 overexpression/siRNA knockdown, western blot for β-catenin, β-catenin rescue experiments, xenograft mouse model\",\n      \"journal\": \"Molecular and cellular probes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by rescue experiment, in vivo xenograft, single lab\",\n      \"pmids\": [\"32334007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sox30 in Nile tilapia localizes to spermatocytes and spermatids in the testis and directly regulates transcription of spermiogenesis-related genes ift140 and ptprb by binding to their promoters; CRISPR/Cas9-mediated sox30 mutation causes abnormal spermiogenesis, reduced sperm motility, and male subfertility.\",\n      \"method\": \"CRISPR/Cas9 knockout, ChIP-seq, ChIP-PCR, luciferase reporter assay, comparative transcriptome analysis\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and luciferase reporter for direct target gene activation, clean genetic knockout with phenotype, single lab in teleost model\",\n      \"pmids\": [\"34801758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SOX30 directly binds to SYCE1 and SYCE2 promoters to activate their transcription, regulating synaptonemal complex (SC) assembly; Sox30 knockout mice show defects in SC central element distribution (SYCE1, SYCE2, TEX12), impaired DNA double-strand break repair, persistence of RAD51 and RPA2 in late spermatocytes, and reduced crossover formation.\",\n      \"method\": \"Sox30-knockout mice, chromosome spreading, ChIP for SYCE1/SYCE2 promoters, immunofluorescence for SC components and recombination proteins, transcriptome co-expression analysis, Sox30 re-expression rescue\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct promoter binding by ChIP, multiple SC and HR marker readouts, in vivo rescue by SOX30 re-expression, multiple orthogonal methods\",\n      \"pmids\": [\"41467312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A human SOX30 stop-gained mutation (Arg478*) produces a C-terminal truncated protein with dramatically reduced association with HDAC3; missense mutations in the HMG domain reduce SOX30 DNA-binding ability; a P353S missense mutation modeled in mice (P382S knock-in) causes defects in late spermatocyte stages and reduces mature sperm without complete sterility.\",\n      \"method\": \"Genetic screening of NOA patients, in vitro functional assays for protein-protein interaction with HDAC3, DNA-binding assays, Sox30P382S knock-in mouse model\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional validation of mutations, knock-in mouse model with defined phenotype, single lab\",\n      \"pmids\": [\"41269228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PFOS exposure suppresses SOX30 expression in spermatocytes, leading to downregulation of its downstream targets RPA2 and RAD51 (key homologous recombination repair proteins), resulting in unrepaired DNA double-strand breaks and spermatocyte apoptosis; overexpression of SOX30 in PFOS-exposed GC2 cells restores RPA2/RAD51 expression and rescues DSB repair capacity.\",\n      \"method\": \"In vitro PFOS treatment of GC2 spermatocyte cells, SOX30 overexpression rescue, western blot for RPA2/RAD51, chromosome spreading with high-resolution microscopy\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular readouts, mechanistic rescue in cell line, single lab\",\n      \"pmids\": [\"41905031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SOX30 suppresses ovarian cancer cell proliferation primarily through an autophagy-mediated mechanism rather than apoptosis; SOX30 overexpression induces marked autophagy and co-expression analysis links SOX30 to key autophagy-related genes.\",\n      \"method\": \"MTS assay, colony formation assay, flow cytometry, western blotting, confocal microscopy for autophagy, xenograft model, co-expression analysis\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with autophagy mechanistic readout, in vivo xenograft, single lab\",\n      \"pmids\": [\"41566108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SOX30 expression in mouse testis is regulated by DNA methylation status at its CpG island promoter; Sox30 is hypo-methylated in testis (where it is expressed) and hypermethylated in other tissues (where it is silenced); demethylation with 5-aza-dC restores Sox30 expression in GC2, TM3, and TM4 cell lines.\",\n      \"method\": \"Methylation-specific PCR, bisulfite sequencing, 5-aza-dC demethylation treatment, RT-PCR expression analysis across tissues\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological demethylation rescue confirms epigenetic regulation, multiple tissue comparisons, single lab\",\n      \"pmids\": [\"24810894\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SOX30 is a testis-enriched transcription factor (containing an HMG-box DNA-binding domain) that is essential for spermatogenesis: it binds specific promoter sequences to directly activate postmeiotic haploid gene programs (including synaptonemal complex genes SYCE1/SYCE2 and spermatid-specific genes), regulates its own transcription, associates with HDAC3 via its C-terminus, and in somatic cancer contexts acts as a tumor suppressor by directly activating p53 transcription and suppressing Wnt/β-catenin signaling through both transcriptional repression of β-catenin and protein-level competition with TCF for β-catenin binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SOX30 is an HMG-box transcription factor that functions as a master regulator of postmeiotic spermatogenesis and, in somatic tissues, as a tumor suppressor [#1, #3, #2]. In the testis, SOX30 is essential for the transition through round spermatid differentiation: Sox30-null males are completely sterile, arresting at step 3 spermiogenesis with aberrant acrosome and axoneme development and multinucleated symplasts, while females are unaffected [#1]. SOX30 establishes a core postmeiotic gene program beginning in late meiosis, binding specific DNA sequences genome-wide to drive expression of spermatid genes such as Tnp1, Hils1, Ccdc54 and Tsks [#3], and it directly activates the synaptonemal complex genes SYCE1 and SYCE2 to support central-element assembly, DNA double-strand break repair and crossover formation [#12]. SOX30 expression is itself controlled at multiple levels: it is restricted to testis by CpG-island promoter methylation [#16], induced by retinoic acid and MYBL1, and reinforced by direct autoregulation of its own promoter [#4]. Promoter hypermethylation silences SOX30 in non-obstructive azoospermia, and adeno-associated-virus re-expression of Sox30 in null adult mice restores spermatogenesis and fertility, establishing a causal link to male infertility [#7]; a human stop-gained mutation (Arg478*) abolishes association with HDAC3 and HMG-domain missense mutations impair DNA binding [#13]. In cancer, SOX30 acts as a tumor suppressor through two principal axes: it directly binds and transactivates the p53 promoter [#0], and it antagonizes Wnt/\\u03b2-catenin signaling both by transcriptionally repressing \\u03b2-catenin and by binding \\u03b2-catenin protein through its amino-terminus to compete with TCF [#2]. SOX30 is post-transcriptionally repressed by microRNAs including miR-645 and miR-653-5p in hepatocellular, prostate and other cancers [#6, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that SOX30 tissue-restricted expression is set epigenetically, explaining why this factor is testis-specific.\",\n      \"evidence\": \"Methylation-specific PCR, bisulfite sequencing and 5-aza-dC demethylation rescue across mouse tissues and cell lines\",\n      \"pmids\": [\"24810894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the demethylating machinery in testis\", \"Does not link methylation state to a downstream transcriptional program\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined SOX30 as a direct transcriptional activator of p53, providing the first molecular mechanism for its tumor-suppressor activity.\",\n      \"evidence\": \"ChIP at the p53 promoter, ectopic expression/knockdown with proliferation and apoptosis readouts, and in vivo tumor formation in lung cancer cells\",\n      \"pmids\": [\"25435374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lung-cancer context\", \"Does not address whether tumor suppression requires p53 in all cell types\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated by clean knockout that SOX30 is absolutely required for the round spermatid stage, defining its essential developmental role.\",\n      \"evidence\": \"Sox30 knockout mouse with histological staging of spermatogenesis\",\n      \"pmids\": [\"29247201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify direct target genes at this stage\", \"Mechanism of symplast formation unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the genome-wide targets of SOX30, showing it directly drives a defined postmeiotic gene program initiated in late meiosis.\",\n      \"evidence\": \"ChIP-seq plus stage-specific transcriptomics in Sox30 mutant mouse spermatogenic cells\",\n      \"pmids\": [\"29866902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-factors directing SOX30 occupancy not defined\", \"Consensus binding motif vs. cancer ACAAT/CACTTTG motifs not reconciled\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed SOX30 antagonizes Wnt/\\u03b2-catenin signaling through dual transcriptional and protein-level mechanisms, mapping the responsible domains.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, TOP/FOP reporter, domain-deletion mutants, and in vivo metastasis/knockout models in lung cancer\",\n      \"pmids\": [\"29739711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of \\u03b2-catenin/TCF competition not determined\", \"Relative contribution of repression vs. sequestration in vivo unquantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established autoregulation and upstream control of SOX30 transcription, embedding it in the retinoic acid/MYBL1 meiotic entry circuit.\",\n      \"evidence\": \"Promoter reporter assays, ChIP for self-binding, and retinoic acid treatment in Sox30 knockout mice\",\n      \"pmids\": [\"29848638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MYBL1 regulation inferred from knockout context rather than direct binding\", \"Quantitative role of autoregulation in expression timing unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended SOX30 tumor suppression to direct activation of desmosomal genes, linking it to cell-adhesion control of Wnt and ERK signaling.\",\n      \"evidence\": \"ChIP at the ACAAT motif of DSP/JUP/DSC3 promoters, functional assays, and SOX30-knockout carcinogenesis model in lung adenocarcinoma\",\n      \"pmids\": [\"29855376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanistic link between desmosomal genes and signaling not fully dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified miR-645 as an upstream repressor of SOX30, extending its p53-activating tumor-suppressor axis to hepatocellular carcinoma.\",\n      \"evidence\": \"Luciferase 3'-UTR reporter, gain/loss-of-function, and ChIP for p53 promoter binding\",\n      \"pmids\": [\"30312695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single context\", \"Does not establish in vivo relevance of the miRNA axis\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided causal in vivo proof that SOX30 silencing underlies human azoospermia and that restoring it rescues fertility.\",\n      \"evidence\": \"Genome-wide methylation profiling of NOA testes plus AAV-mediated Sox30 re-expression in null adult mice with offspring analysis\",\n      \"pmids\": [\"31835093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Frequency of SOX30 methylation across NOA cohorts not established\", \"Therapeutic translatability untested in human tissue\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed conserved transcriptional control of SOX30 in spermatogenesis by Dmrt1 in a teleost, and added miR-653-5p as another repressor in cancer.\",\n      \"evidence\": \"EMSA/ChIP-PCR/reporter for Dmrt1 binding in Nile tilapia; dual-luciferase and functional assays for miR-653-5p in prostate cancer\",\n      \"pmids\": [\"31690021\", \"31889959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cross-species conservation of Dmrt1 regulation in mammals untested\", \"miR-653-5p axis shown in single cell context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed SOX30 genetically upstream of \\u03b2-catenin in leukemia, generalizing its Wnt-suppressor role beyond solid tumors.\",\n      \"evidence\": \"Overexpression/knockdown, \\u03b2-catenin rescue epistasis, and xenografts in acute myeloid leukemia cells\",\n      \"pmids\": [\"32334007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to \\u03b2-catenin promoter in AML not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated conserved direct target-gene activation by Sox30 driving spermiogenesis in a teleost model.\",\n      \"evidence\": \"CRISPR/Cas9 knockout, ChIP-seq/ChIP-PCR and reporter assays for ift140 and ptprb in Nile tilapia\",\n      \"pmids\": [\"34801758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian orthology of ift140/ptprb regulation untested\", \"Subfertility vs. mouse sterility difference unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed an earlier meiotic role for SOX30 in synaptonemal complex assembly and recombination, predating its postmeiotic function.\",\n      \"evidence\": \"Sox30-knockout chromosome spreads, ChIP at SYCE1/SYCE2 promoters, immunofluorescence for SC/recombination markers and re-expression rescue\",\n      \"pmids\": [\"41467312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SOX30 coordinates meiotic and postmeiotic programs unclear\", \"Direct vs. indirect effect on RAD51/RPA2 persistence not fully separated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected human SOX30 coding mutations to infertility and mapped the functional consequences of HMG-domain and C-terminal lesions.\",\n      \"evidence\": \"NOA patient genetic screening, in vitro HDAC3-interaction and DNA-binding assays, and a Sox30 P382S knock-in mouse\",\n      \"pmids\": [\"41269228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the SOX30\\u2013HDAC3 interaction in vivo undefined\", \"Genotype\\u2013phenotype correlation in larger cohorts lacking\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified SOX30 as a node linking environmental toxicant exposure to homologous-recombination repair failure in spermatocytes.\",\n      \"evidence\": \"PFOS treatment of GC2 cells with SOX30 overexpression rescue and RPA2/RAD51 readouts plus chromosome spreading\",\n      \"pmids\": [\"41905031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo PFOS-SOX30 axis not tested\", \"Mechanism of PFOS-induced SOX30 suppression unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended SOX30 tumor suppression to an autophagy-dependent rather than apoptotic mechanism in ovarian cancer.\",\n      \"evidence\": \"Proliferation/colony/flow assays, autophagy confocal imaging, co-expression analysis and xenografts\",\n      \"pmids\": [\"41566108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct autophagy gene targets not identified\", \"Relationship to p53/Wnt axes unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SOX30 partitions between its meiotic, postmeiotic and somatic tumor-suppressor programs through context-specific cofactors and binding motifs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of SOX30 on DNA or with \\u03b2-catenin/HDAC3\", \"Cofactors directing tissue-specific occupancy unknown\", \"Reconciliation of distinct binding motifs (CACTTTG, ACAAT, SC promoters) lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 3, 5, 12]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 3, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [1, 3, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CTNNB1\", \"HDAC3\", \"TCF\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}