KDM5C and KDM5D mutations have different and opposing consequences in ccRCC cells [RNASeq_single_KO]

KDM5C is commonly mutated in ccRCC tumours 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 nonoverlapping 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 rescued by co-mutation of KDM5C. This unexpected antagonistic relationship between KDM5C and KDM5D is 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 genes. Consistent with the tumour growth phenotype, KDM5D mutation induced the upregulation of putative tumour suppressor genes and downregulation of putative pro-proliferative genes. These transcriptional effects were also reversed by co-mutation of KDM5C. While KDM5C and KDM5D bind to at least some overlapping genomic sites, we identify that gene expression changes induced by KDM5C or KDM5D mutation are apparently unrelated to the direct functions of these proteins at the relevant gene promoters or enhancers. Our findings identify similarities and differences in KDM5C and KDM5D functions, challenging the idea that KDM5D in male cells functions equivalently to the second KDM5C allele in female cells, and implicate an interplay between KDM5C mutation and Y chromosome loss in ccRCC development in men.