TY  - JOUR
AU  - Müller, Marvin
AU  - Zodel, Kyra
AU  - Abhari, Behnaz A
AU  - Cuomo, Francesca
AU  - Nizamuddin, Sheikh
AU  - Metzger, Patrick
AU  - Börries, Melanie
AU  - Timmers, Hermanus Theodorus Marcus
AU  - Frew, Ian J
TI  - KDM5C and KDM5D mutations have different consequences in clear cell renal cell carcinoma cells.
JO  - Communications biology
VL  - 8
IS  - 1
SN  - 2399-3642
CY  - London
PB  - Springer Nature
M1  - DKFZ-2025-00366
SP  - 244
PY  - 2025
AB  - 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 genes. While KDM5C and KDM5D bind to at least some overlapping genomic sites, 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.
KW  - Carcinoma, Renal Cell: genetics
KW  - Carcinoma, Renal Cell: pathology
KW  - Humans
KW  - Kidney Neoplasms: genetics
KW  - Kidney Neoplasms: pathology
KW  - Histone Demethylases: genetics
KW  - Histone Demethylases: metabolism
KW  - Mutation
KW  - Male
KW  - Female
KW  - Cell Line, Tumor
KW  - Animals
KW  - Mice
KW  - Gene Expression Regulation, Neoplastic
KW  - Chromosomes, Human, Y: genetics
KW  - Minor Histocompatibility Antigens
KW  - KDM5C protein, human (NLM Chemicals)
KW  - Histone Demethylases (NLM Chemicals)
KW  - KDM5D protein, human (NLM Chemicals)
KW  - Minor Histocompatibility Antigens (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39955388
C2  - pmc:PMC11830100
DO  - DOI:10.1038/s42003-025-07695-8
UR  - https://inrepo02.dkfz.de/record/298932
ER  -