PLZF, a Tumor Suppressor Genetically Lost in Metastatic Castration-Resistant Prostate Cancer, Is a Mediator of Resistance to Androgen Deprivation Therapy.

Publication Type:

Journal Article

Authors:

Hsieh, Chen-Lin; Botta, Ginevra; Gao, Shuai; Li, Tiantian; Van Allen, Eliezer M; Treacy, Daniel J; Cai, Changmeng; He, Housheng Hansen; Sweeney, Christopher J; Brown, Myles; Balk, Steven P; Nelson, Peter S; Garraway, Levi A; Kantoff, Philip W

Source:

Cancer research, Volume 75, Issue 10, p.1944-8 (2015)

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.