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@ARTICLE{Mller:298932,
author = {M. Müller and K. Zodel and B. A. Abhari and F. Cuomo and
S. Nizamuddin and P. Metzger and M. Börries$^*$ and H. T.
M. Timmers$^*$ and I. J. Frew$^*$},
title = {{KDM}5{C} and {KDM}5{D} mutations have different
consequences in clear cell renal cell carcinoma cells.},
journal = {Communications biology},
volume = {8},
number = {1},
issn = {2399-3642},
address = {London},
publisher = {Springer Nature},
reportid = {DKFZ-2025-00366},
pages = {244},
year = {2025},
abstract = {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.},
keywords = {Carcinoma, Renal Cell: genetics / Carcinoma, Renal Cell:
pathology / Humans / Kidney Neoplasms: genetics / Kidney
Neoplasms: pathology / Histone Demethylases: genetics /
Histone Demethylases: metabolism / Mutation / Male / Female
/ Cell Line, Tumor / Animals / Mice / Gene Expression
Regulation, Neoplastic / Chromosomes, Human, Y: genetics /
Minor Histocompatibility Antigens / KDM5C protein, human
(NLM Chemicals) / Histone Demethylases (NLM Chemicals) /
KDM5D protein, human (NLM Chemicals) / Minor
Histocompatibility Antigens (NLM Chemicals)},
cin = {FR01},
ddc = {570},
cid = {I:(DE-He78)FR01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39955388},
pmc = {pmc:PMC11830100},
doi = {10.1038/s42003-025-07695-8},
url = {https://inrepo02.dkfz.de/record/298932},
}