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: Shu-Ting Chen, Maiko Okada, Ryuichiro Nakato, Kosuke Izumi, Masashige Bando, Katsuhiko Shirahige
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 35 Pg. 21713-23 (Aug 28 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26175158 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• AR protein, human
• Androgens
• Chromatin
• Receptors, Androgen
• USP7 protein, human
• Ubiquitin Thiolesterase
• Ubiquitin-Specific Peptidase 7

Topics

• Androgens (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromatin (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Protein Binding (drug effects)
• Receptors, Androgen (metabolism)
• Response Elements (genetics)
• Ubiquitin Thiolesterase (metabolism)
• Ubiquitin-Specific Peptidase 7
• Ubiquitination (drug effects)