title: TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer.
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.
authors.affiliation: 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.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Groner
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Cato
authors.affiliation: 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.
authors.forename: Jonas
authors.initials: J
authors.lastname: de Tribolet-Hardy
authors.affiliation: Institute of Oncology Research, Bellinzona 6500, Switzerland.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bernasocchi
authors.affiliation: Institute of Oncology Research, Bellinzona 6500, Switzerland.
authors.forename: Hana
authors.initials: H
authors.lastname: Janouskova
authors.affiliation: PamGene International, Den Bosch 521HH, the Netherlands.
authors.forename: Diana
authors.initials: D
authors.lastname: Melchers
authors.affiliation: PamGene International, Den Bosch 521HH, the Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Houtman
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
authors.forename: Andrew C B
authors.initials: ACB
authors.lastname: Cato
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tschopp
authors.affiliation: Division of Newborn Medicine, Children's Hospital Boston and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Corsinotti
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland; Department of Urology, University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Fankhauser
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Fritz
authors.affiliation: Department of Urology, University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Cédric
authors.initials: C
authors.lastname: Poyet
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wagner
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich 8093, Switzerland.
authors.forename: Tiannan
authors.initials: T
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.affiliation: 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.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.affiliation: 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.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Theurillat
authors.affiliation: 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.
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C410798:AR protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D012097:Repressor Proteins; C509761:SPOP protein, human; C555317:TRIM24 protein, human