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J Biol Chem. 2015 Aug 28;290(35):21713-23. doi: 10.1074/jbc.M114.628255. Epub 2015 Jul 14.

The Deubiquitinating Enzyme USP7 Regulates Androgen Receptor Activity by Modulating Its Binding to Chromatin.

Author information

1
From the Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032 and.
2
the Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan.
3
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.

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.

KEYWORDS:

androgen receptor; gene transcription; prostate cancer; transcriptional coactivator; ubiquitin-dependent protease

PMID:
26175158
PMCID:
PMC4571893
DOI:
10.1074/jbc.M114.628255
[Indexed for MEDLINE]
Free PMC Article

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