Androgen receptoristhe keytranscriptional mediatorofthe tumor suppressor SPOP in prostate cancer

Chuandong Geng, Kimal Rajapakshe, Shrijal S. Shah, John Shou, Vijay Kumar Eedunuri, Christopher Foley, Warren Fiskus, Mahitha Rajendran, Sue Anne Chew, Martin Zimmermann, Richard Bond, Bin He, Cristian Coarfa, Nicholas Mitsiades

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Somatic missense mutations in the substrate-binding pocket of the E3 ubiquitin ligase adaptor SPOP are present in up to 15% of human prostate adenocarcinomas, but are rare in other malignancies, suggesting a prostate-specific mechanism of action. SPOP promotes ubiquitination and degradation of several protein substrates, including the androgen receptor (AR) coactivator SRC-3. However, the relative contributions that SPOP substrates may make to the pathophysiology of SPOP-mutant (mt) prostate adenocarcinomas are unknown. Using an unbiased bioinformatics approach, we determined that the gene expression profile of prostate adenocarcinoma cells engineered to express mt-SPOP overlaps greatly with the gene signature of both SRC-3 and AR transcriptional output, with a stronger similarity to AR than SRC-3. This finding suggests that in addition to its SRC-3-mediated effects, SPOP also exerts SRC-3-independent effects that are AR-mediated. Indeed, we found that wild-type (wt) but not prostate adenocarcinoma-associated mutants of SPOP promoted AR ubiquitination and degradation, acting directly through a SPOP-binding motif in the hinge region of AR. In support of these results, tumor xenografts composed of prostate adenocarcinoma cells expressing mt-SPOP exhibited higher AR protein levels and grew faster than tumors composed of prostate adenocarcinoma cells expressing wt-SPOP. Furthermore, genetic ablation of SPOP was sufficient to increase AR protein levels in mouse prostate. Examination of public human prostate adenocarcinoma datasets confirmed a strong link between transcriptomic profiles of mt-SPOP and AR. Overall, our studies highlight the AR axis as the key transcriptional output of SPOP in prostate adenocarcinoma and provide an explanation for the prostate-specific tumor suppressor role of wt-SPOP.

Original languageEnglish (US)
Pages (from-to)5631-5643
Number of pages13
JournalCancer research
Volume74
Issue number19
DOIs
StatePublished - Oct 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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