TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer

Publication date: Available online 26 May 2016
Source:Cancer Cell
Author(s): 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
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.

Graphical abstract

Teaser

Groner et al. show that recurrent prostate cancer-driver mutations in SPOP stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling; AR and TRIM24 co-activated genes are upregulated in the castration-resistant state and are predictive of disease recurrence.


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