Groner Anna C, Cato Laura, de Tribolet-Hardy Jonas, Bernasocchi Tiziano, Janouskova Hana, Melchers Diana, Houtman René, Cato Andrew C B, Tschopp Patrick, Gu Lei, Corsinotti Andrea, Zhong Qing, Fankhauser Christian, Fritz Christine, Poyet Cédric, Wagner Ulrich, Guo Tiannan, Aebersold Ruedi, Garraway Levi A, Wild Peter J, Theurillat Jean-Philippe, Brown Myles
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Institute of Oncology Research, Bellinzona 6500, Switzerland.
Cancer Cell. 2016 Jun 13;29(6):846-858. doi: 10.1016/j.ccell.2016.04.012. Epub 2016 May 26.
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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