RT Journal Article
SR Electronic
T1 PLZF, a Tumor Suppressor Genetically Lost in Metastatic Castration-Resistant Prostate Cancer, Is a Mediator of Resistance to Androgen Deprivation Therapy
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 1944
OP 1948
DO 10.1158/0008-5472.CAN-14-3602
VO 75
IS 10
A1 Hsieh, Chen-Lin
A1 Botta, Ginevra
A1 Gao, Shuai
A1 Li, Tiantian
A1 Van Allen, Eliezer M.
A1 Treacy, Daniel J.
A1 Cai, Changmeng
A1 He, Housheng Hansen
A1 Sweeney, Christopher J.
A1 Brown, Myles
A1 Balk, Steven P.
A1 Nelson, Peter S.
A1 Garraway, Levi A.
A1 Kantoff, Philip W.
YR 2015
UL http://cancerres.aacrjournals.org/content/75/10/1944.abstract
AB 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.