biostudies-literatureBrooke GNAcademy of FinlandRosetrees TrustMinistry of Science and Education, Republic of AzerbaijanRCUK | MRC | Medical Research FoundationSigrid Juséliuksen SäätiöMedical Research CouncilThe Urology Foundation/John Black Charitable Foundation and Wellcome Institutional Strategic Support FundRCUK | Biotechnology and Biological Sciences Research CouncilProstate Cancer UKKing Faisal Specialist Hospital and Research CentreBiotechnology and Biological Sciences Research CouncilSyöpäjärjestöt757-773https://www.ebi.ac.uk/biostudies/studies/S-EPMC12909129biostudies-literatureUnknown45(8)Prostate cancer is dependent upon the androgen receptor (AR), the activity of which is modified by cofactors that either enhance or repress its activity, often in a context-dependent manner. FUS/TLS is a multifunctional protein known to be important in multiple cancer types; in prostate cancer, we previously showed that FUS has a potential tumour suppressor role. Here, transcriptomic analysis of the LNCaP prostate cancer cell line shows a significant overlap in genes regulated by FUS and the androgen receptor. We demonstrate that FUS can regulate androgen receptor activity, in either direction, but predominantly represses androgen signalling. Reporter assays and domain-specific analyses of FUS identified mechanisms by which FUS modifies androgen receptor activity. FUS interacts with the anOncogeneDisruption of androgen receptor-cofactor interactions by the RNA-binding protein FUS/TLS alters androgen signalling in prostate cancer.PMC12909129BB/X018997/1BB/W020033/1BB/X511171/1Bevan CLWaxman JBrooke GNLeach DAAlkheilewi MAPine ACFioretti FMRees EPowell SMReader CSLatonen LCulley RLVisakorpi TAzadova AReebye VfalseDisruption of androgen receptor-cofactor interactions by the RNA-binding protein FUS/TLS alters androgen signalling in prostate cancer.Prostate cancer is dependent upon the androgen receptor (AR), the activity of which is modified by cofactors that either enhance or repress its activity, often in a context-dependent manner. FUS/TLS is a multifunctional protein known to be important in multiple cancer types; in prostate cancer, we previously showed that FUS has a potential tumour suppressor role. Here, transcriptomic analysis of the LNCaP prostate cancer cell line shows a significant overlap in genes regulated by FUS and the androgen receptor. We demonstrate that FUS can regulate androgen receptor activity, in either direction, but predominantly represses androgen signalling. Reporter assays and domain-specific analyses of FUS identified mechanisms by which FUS modifies androgen receptor activity. FUS interacts with the an2026-01-01T00:00:00Z2026 Mar2026-07-16T05:04:16.738Z2026-07-09T10:37:14.475ZS-EPMC129091294165198610.1038/s41388-026-03682-3