Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer

Shan Wang, Rahul K. Kollipara, Nishi Srivastava, Rui Li, Preethi Ravindranathan, Elizabeth Hernandez, Eva Freeman, Caroline G. Humphries, Payal Kapur, Yair Lotan, Ladan Fazli, Martin E. Gleave, Stephen R. Plymate, Ganesh Raj, Jer-Tsong Hsieh, Ralf Kittler

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

The transcription factor E-twenty-six related gene (ERG), which is overexpressed through gene fusion with the androgen-responsive gene transmembrane protease, serine 2 (TMPRSS2) in ̃40% of prostate tumors, is a key driver of prostate carcinogenesis. Ablation of ERG would disrupt a key oncogenic transcriptional circuit and could be a promising therapeutic strategy for prostate cancer treatment. Here, we show that ubiquitin-specific peptidase 9, X-linked (USP9X), a deubiquitinase enzyme, binds ERG in VCaP prostate cancer cells expressing TMPRSS2-ERG and deubiquitinates ERG in vitro. USP9X knockdown resulted in increased levels of ubiquitinated ERG and was coupled with depletion of ERG. Treatment with the USP9X inhibitor WP1130 resulted in ERG degradation both in vivo and in vitro, impaired the expression of genes enriched in ERG and prostate cancer relevant gene signatures in microarray analyses, and inhibited growth of ERG-positive tumors in three mouse xenograft models. Thus, we identified USP9X as a potential therapeutic target in prostate cancer cells and established WP1130 as a lead compound for the development of ERGdepleting drugs.

Original languageEnglish (US)
Pages (from-to)4251-4256
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number11
DOIs
StatePublished - Mar 18 2014

ASJC Scopus subject areas

  • General

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