TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer

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

doi:10.1016/j.ccell.2016.04.012

TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer

Cancer Cell. 2016 Jun 13;29(6):846-858. doi: 10.1016/j.ccell.2016.04.012. Epub 2016 May 26.

Authors

Anna C Groner¹, Laura Cato¹, Jonas de Tribolet-Hardy¹, Tiziano Bernasocchi², Hana Janouskova², Diana Melchers³, René Houtman³, Andrew C B Cato⁴, Patrick Tschopp⁵, Lei Gu⁶, Andrea Corsinotti⁷, Qing Zhong⁸, Christian Fankhauser⁹, Christine Fritz⁸, Cédric Poyet¹⁰, Ulrich Wagner⁸, Tiannan Guo¹¹, Ruedi Aebersold¹², Levi A Garraway¹³, Peter J Wild⁸, Jean-Philippe Theurillat¹⁴, Myles Brown¹⁵

Affiliations

¹ 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.
² Institute of Oncology Research, Bellinzona 6500, Switzerland.
³ PamGene International, Den Bosch 521HH, the Netherlands.
⁴ Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
⁵ Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
⁶ Division of Newborn Medicine, Children's Hospital Boston and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
⁷ 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.
⁸ Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
⁹ Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland; Department of Urology, University Hospital Zurich, Zurich 8091, Switzerland.
¹⁰ Department of Urology, University Hospital Zurich, Zurich 8091, Switzerland.
¹¹ Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich 8093, Switzerland.
¹² 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.
¹³ 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.
¹⁴ 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: jeanp_theurillat@ior.iosi.ch.
¹⁵ 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: myles_brown@dfci.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carrier Proteins / chemistry
Carrier Proteins / genetics*
Carrier Proteins / metabolism
Cell Proliferation
Disease Progression
Gene Expression Regulation, Neoplastic
Humans
Male
Neoplasm Transplantation
Nuclear Proteins / genetics*
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Prostatic Neoplasms, Castration-Resistant / genetics*
Prostatic Neoplasms, Castration-Resistant / metabolism
Prostatic Neoplasms, Castration-Resistant / pathology
Receptors, Androgen / chemistry
Receptors, Androgen / genetics*
Receptors, Androgen / metabolism
Repressor Proteins / genetics*
Signal Transduction

Substances

AR protein, human
Carrier Proteins
Nuclear Proteins
Receptors, Androgen
Repressor Proteins
SPOP protein, human
TRIM24 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding