biostudies-literatureMuller MDeutsche Forschungsgemeinschaft (German Research Foundation)244https://www.ebi.ac.uk/biostudies/studies/S-EPMC11830100biostudies-literatureUnknown8(1)KDM5C is commonly mutated in clear cell renal cell carcinomas (ccRCC) in men but rarely in women. Introducing KDM5C mutation into two male and two female KDM5C wild-type ccRCC cell lines caused different phenotypes and non-overlapping transcriptional consequences, indicative of context-dependent functions of KDM5C. We identify that loss of the Y chromosome, harbouring the KDM5C homologue KDM5D, occurs in most male KDM5C mutant ccRCCs. Mutation of KDM5D in male 786-O cells prevented xenograft tumour formation and this phenotype was unexpectedly rescued by co-mutation of KDM5C, consistent with the co-occurrence of KDM5C mutation and loss of the Y chromosome in ccRCC. Transcriptional analyses showed that KDM5C and KDM5D regulate the expression of both overlapping as well as distinct sets of gCommunications biologyKDM5C and KDM5D mutations have different consequences in clear cell renal cell carcinoma cells.PMC1183010042490703431984000441891347493802833Frew IJMuller MCuomo FBoerries MAbhari BAZodel KTimmers HTMNizamuddin SMetzger PfalseKDM5C and KDM5D mutations have different consequences in clear cell renal cell carcinoma cells.KDM5C is commonly mutated in clear cell renal cell carcinomas (ccRCC) in men but rarely in women. Introducing KDM5C mutation into two male and two female KDM5C wild-type ccRCC cell lines caused different phenotypes and non-overlapping transcriptional consequences, indicative of context-dependent functions of KDM5C. We identify that loss of the Y chromosome, harbouring the KDM5C homologue KDM5D, occurs in most male KDM5C mutant ccRCCs. Mutation of KDM5D in male 786-O cells prevented xenograft tumour formation and this phenotype was unexpectedly rescued by co-mutation of KDM5C, consistent with the co-occurrence of KDM5C mutation and loss of the Y chromosome in ccRCC. Transcriptional analyses showed that KDM5C and KDM5D regulate the expression of both overlapping as well as distinct sets of g2025-01-01T00:00:00Z2025 Feb2026-06-02T20:03:32.163Z2025-04-07T07:50:03.741ZS-EPMC118301003995538810.1038/s42003-025-07695-8