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Cancer Res. 2015 May 15;75(10):1944-8. doi: 10.1158/0008-5472.CAN-14-3602. Epub 2015 Mar 25.

PLZF, a tumor suppressor genetically lost in metastatic castration-resistant prostate cancer, is a mediator of resistance to androgen deprivation therapy.

Author information

1
Department of Medical Oncology, and.
2
Department of Medical Oncology, and Broad Institute, Cambridge, Massachusetts.
3
Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
4
Department of Medical Oncology, and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
5
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
6
Division of Clinical Research, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
7
Department of Medical Oncology, and Broad Institute, Cambridge, Massachusetts. philip_kantoff@dfci.harvard.edu levi_garraway@dfci.harvard.edu.
8
Department of Medical Oncology, and philip_kantoff@dfci.harvard.edu levi_garraway@dfci.harvard.edu.

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.

PMID:
25808865
PMCID:
PMC4433564
DOI:
10.1158/0008-5472.CAN-14-3602
[Indexed for MEDLINE]
Free PMC Article

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