title: PLZF, a tumor suppressor genetically lost in metastatic castration-resistant prostate cancer, is a mediator of resistance to androgen deprivation therapy.
abstract: Whole-exome sequencing of metastatic castration-resistant prostate cancer (mCRPC) reveals that 5% to 7% of tumors harbor promyelocytic leukemia zinc finger (PLZF) protein homozygous deletions. PLZF is a canonical androgen-regulated putative tumor suppressor gene whose expression is inhibited by androgen deprivation therapy (ADT). Here, we demonstrate that knockdown of PLZF expression promotes a CRPC and enzalutamide-resistant phenotype in prostate cancer cells. Reintroduction of PLZF expression is sufficient to reverse androgen-independent growth mediated by PLZF depletion. PLZF loss enhances CRPC tumor growth in a xenograft model. Bioinformatic analysis of the PLZF cistrome shows that PLZF negatively regulates multiple pathways, including the MAPK pathway. Accordingly, our data support an oncogenic program activated by ADT. This acquired mechanism together with the finding of genetic loss in CRPC implicates PLZF inactivation as a mechanism promoting ADT resistance and the CRPC phenotype.
authors: Department of Medical Oncology, and.
authors: Chen-Lin
authors: CL
authors: Hsieh
authors: Department of Medical Oncology, and Broad Institute, Cambridge, Massachusetts.
authors: Ginevra
authors: G
authors: Botta
authors: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors: Shuai
authors: S
authors: Gao
authors: Department of Medical Oncology, and.
authors: Tiantian
authors: T
authors: Li
authors: Department of Medical Oncology, and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors: Eliezer M
authors: EM
authors: Van Allen
authors: Department of Medical Oncology, and.
authors: Daniel J
authors: DJ
authors: Treacy
authors: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors: Changmeng
authors: C
authors: Cai
authors: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors: Housheng Hansen
authors: HH
authors: He
authors: Department of Medical Oncology, and.
authors: Christopher J
authors: CJ
authors: Sweeney
authors: Department of Medical Oncology, and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors: Myles
authors: M
authors: Brown
authors: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors: Steven P
authors: SP
authors: Balk
authors: Division of Clinical Research, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
authors: Peter S
authors: PS
authors: Nelson
authors: Department of Medical Oncology, and Broad Institute, Cambridge, Massachusetts. philip_kantoff@dfci.harvard.edu levi_garraway@dfci.harvard.edu.
authors: Levi A
authors: LA
authors: Garraway
authors: Department of Medical Oncology, and philip_kantoff@dfci.harvard.edu levi_garraway@dfci.harvard.edu.
authors: Philip W
authors: PW
authors: Kantoff
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D008819:Mice, Nude; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; D051741:Kruppel-Like Transcription Factors; D009570:Nitriles; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C092037:ZBTB16 protein, human; D010669:Phenylthiohydantoin; C540278:enzalutamide