title: The Deubiquitinating Enzyme USP7 Regulates Androgen Receptor Activity by Modulating Its Binding to Chromatin.
abstract: The androgen receptor (AR), a nuclear receptor superfamily transcription factor, plays a key role in prostate cancer. AR signaling is the principal target for prostate cancer treatment, but current androgen-deprivation therapies cannot completely abolish AR signaling because of the heterogeneity of prostate cancers. Therefore, unraveling the mechanism of AR reactivation in androgen-depleted conditions can identify effective prostate cancer therapeutic targets. Increasing evidence indicates that AR activity is mediated by the interplay of modifying/demodifying enzymatic co-regulators. To better understand the mechanism of AR transcriptional activity regulation, we used antibodies against AR for affinity purification and identified the deubiquitinating enzyme ubiquitin-specific protease 7, USP7 as a novel AR co-regulator in prostate cancer cells. We showed that USP7 associates with AR in an androgen-dependent manner and mediates AR deubiquitination. Sequential ChIP assays indicated that USP7 forms a complex with AR on androgen-responsive elements of target genes upon stimulation with the androgen 5α-dihydrotestosterone. Further investigation indicated that USP7 is necessary to facilitate androgen-activated AR binding to chromatin. Transcriptome profile analysis of USP7-knockdown LNCaP cells also revealed the essential role of USP7 in the expression of a subset of androgen-responsive genes. Hence, inhibition of USP7 represents a compelling therapeutic strategy for the treatment of prostate cancer.
authors.affiliation: From the Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032 and.
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Chen
authors.affiliation: the Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Okada
authors.affiliation: From the Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032 and.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Nakato
authors.affiliation: From the Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032 and.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Izumi
authors.affiliation: From the Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032 and.
authors.forename: Masashige
authors.initials: M
authors.lastname: Bando
authors.affiliation: From the Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032 and kshirahi@iam.u-tokyo.ac.jp.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shirahige
mesh_terms: D000728:Androgens / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C410798:AR protein, human; D000728:Androgens; D002843:Chromatin; D011944:Receptors, Androgen; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7
keywords: androgen receptor; gene transcription; prostate cancer; transcriptional coactivator; ubiquitin-dependent protease