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.
Cancer cell. 2016 May 24 [Epub ahead of print]
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
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., 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., 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., Institute of Oncology Research, Bellinzona 6500, Switzerland., PamGene International, Den Bosch 521HH, the Netherlands., PamGene International, Den Bosch 521HH, the Netherlands., Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany., Department of Genetics, Harvard Medical School, Boston, MA 02215, USA., Division of Newborn Medicine, Children's Hospital Boston and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA., MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK; Laboratory Animal Resource Center, Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan., Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland., Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland; Department of Urology, University Hospital Zurich, Zurich 8091, Switzerland., Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland., Department of Urology, University Hospital Zurich, Zurich 8091, Switzerland., Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland., Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich 8093, Switzerland., Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich 8093, Switzerland; Faculty of Science, University of Zurich, Zurich 8057, Switzerland., Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA., Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland., Institute of Oncology Research, Bellinzona 6500, Switzerland; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne 1011, Switzerland. Electronic address: ., 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. Electronic address: .