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.
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Authors | Anna 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 |
Journal | Cancer cell
(Cancer Cell)
Vol. 29
Issue 6
Pg. 846-858
(06 13 2016)
ISSN: 1878-3686 [Electronic] United States |
PMID | 27238081
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 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
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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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