Inactivation of ID4 Promotes a CRPC Phenotype with Constitutive AR Activation Through FKBP52

Collection:
Clark Atlanta University Faculty Publications
Title:
Inactivation of ID4 Promotes a CRPC Phenotype with Constitutive AR Activation Through FKBP52
Creator:
Joshi, Jugal Bharat
Patel, Divya
Morton, Derrick J.
Sharma, Pankaj
Zou, Jin,
Bostanthirige, Dhanuska Hewa
Gorantla, Yamini
Nagappan, Peri,
Komaragiri, Shravan Kumar
Sivils, Jeffrey C.
Xie, Huan
Palaniappan, Ravi
Date of Original:
2017-04-01
Subject:
African Americans--Education (Higher)--Georgia
Clark Atlanta University
Location:
United States, Georgia, Fulton County, Atlanta, 33.749, -84.38798
Medium:
articles
Type:
Text
Format:
application/pdf
Description:
Abstract: Castration-resistant prostate cancer (CRPC) is the emergence of prostate cancer cells that have adapted to the androgen-depleted environment of the prostate. In recent years, targeting multiple chaperones and co-chaperones (e.g., Hsp27, FKBP52) that promote androgen receptor (AR) signaling and/or novel AR regulatory mechanisms have emerged as promising alter- native treatments for CRPC. We have shown that inactivation of inhibitor of differentiation 4 (ID4), a dominant-negative helix loop helix protein, promotes de novo steroidogenesis and CRPC with a gene expression signature that resembles constitutive AR activity in castrated mice. In this study, we investigated the underlying mechanism through which loss of ID4 potentiates AR signaling. Proteomic analysis between prostate cancer cell line LNCaP (L+ns) and LNCaP lacking ID4 (L(?)ID4) revealed elevated levels of Hsp27 and FKBP52, suggesting a role for these AR-associated co- chaperones in promoting constitutively active AR signaling in L(?)ID4 cells. Interestingly, protein interaction studies demonstrated a direct interaction between ID4 and the 52-kDa FK506-binding protein (FKBP52) in vitro, but not with AR. An increase in FKBP52-dependent AR transcriptional activity was observed in L(?)ID4 cells. Moreover, pharmacological inhibition of FKBP52-AR signaling, by treatment with MJC13, attenuated the tumor growth, weight, and volume in L(?)ID4 xenografts. Together, our results demonstrate that ID4 selectively regulates AR activity through direct interaction with FKBP52, and its loss, promotes CRPC through FKBP52-mediated AR signaling.
Source: Molecular Oncology
DOI: 10.1002/1878-0261.12028
Metadata URL:
http://hdl.handle.net/20.500.12322/cau.ir:2017_Joshi_et_al
Language:
eng
Original Collection:
Clark Atlanta University Faculty Publications
Holding Institution:
Clark Atlanta University
Rights:

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