PLZF, a Tumor Suppressor Genetically Lost in Metastatic Castration-Resistant Prostate Cancer, Is a Mediator of Resistance to Androgen Deprivation Therapy
Copyright policy )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. Cancer Res; 75(10); 1944–8. ©2015 AACR.
- University of Mary United States
- Broad Institute United States
- Beth Israel Deaconess Medical Center United States
- University of Toronto Canada
- University Health Network Canada
Male, Antineoplastic Agents, Hormonal, Kruppel-Like Transcription Factors, Mice, Nude, Xenograft Model Antitumor Assays, Prostatic Neoplasms, Castration-Resistant, Drug Resistance, Neoplasm, Cell Line, Tumor, Benzamides, Nitriles, Phenylthiohydantoin, Animals, Promyelocytic Leukemia Zinc Finger Protein, Transcriptome, Cell Proliferation
Male, Antineoplastic Agents, Hormonal, Kruppel-Like Transcription Factors, Mice, Nude, Xenograft Model Antitumor Assays, Prostatic Neoplasms, Castration-Resistant, Drug Resistance, Neoplasm, Cell Line, Tumor, Benzamides, Nitriles, Phenylthiohydantoin, Animals, Promyelocytic Leukemia Zinc Finger Protein, Transcriptome, Cell Proliferation
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