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TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer.

Abstract
Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly upregulated in CRPC. Expression of TRIM24 protein increases from primary PC to CRPC, and both TRIM24 protein levels and the AR/TRIM24 gene signature predict disease recurrence. Analyses in CRPC cells reveal that the TRIM24 bromodomain and the AR-interacting motif are essential to support proliferation. These data provide a rationale for therapeutic TRIM24 targeting in SPOP mutant and CRPC patients.
AuthorsAnna C Groner, Laura Cato, Jonas de Tribolet-Hardy, Tiziano Bernasocchi, Hana Janouskova, Diana Melchers, René Houtman, Andrew C B Cato, Patrick Tschopp, Lei Gu, Andrea Corsinotti, Qing Zhong, Christian Fankhauser, Christine Fritz, Cédric Poyet, Ulrich Wagner, Tiannan Guo, Ruedi Aebersold, Levi A Garraway, Peter J Wild, Jean-Philippe Theurillat, Myles Brown
JournalCancer cell (Cancer Cell) Vol. 29 Issue 6 Pg. 846-858 (06 13 2016) ISSN: 1878-3686 [Electronic] United States
PMID27238081 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2016 Elsevier Inc. All rights reserved.
Chemical References
  • AR protein, human
  • Carrier Proteins
  • Nuclear Proteins
  • Receptors, Androgen
  • Repressor Proteins
  • SPOP protein, human
  • TRIM24 protein, human
Topics
  • Animals
  • Carrier Proteins (chemistry, genetics, metabolism)
  • Cell Proliferation
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Neoplasm Transplantation
  • Nuclear Proteins (genetics)
  • Prostatic Neoplasms (genetics, metabolism, pathology)
  • Prostatic Neoplasms, Castration-Resistant (genetics, metabolism, pathology)
  • Receptors, Androgen (chemistry, genetics, metabolism)
  • Repressor Proteins (genetics)
  • Signal Transduction

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