title: Inactivation of ID4 promotes a CRPC phenotype with constitutive AR activation through FKBP52.
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 alternative 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.
authors.affiliation: Center for Cancer Research and Therapeutic Development, Clark Atlanta University, GA, USA.
authors.forename: Jugal Bharat
authors.initials: JB
authors.lastname: Joshi
authors.affiliation: Center for Cancer Research and Therapeutic Development, Clark Atlanta University, GA, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Patel
authors.affiliation: Center for Cancer Research and Therapeutic Development, Clark Atlanta University, GA, USA.
authors.forename: Derrick J
authors.initials: DJ
authors.lastname: Morton
authors.affiliation: Center for Cancer Research and Therapeutic Development, Clark Atlanta University, GA, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Center for Cancer Research and Therapeutic Development, Clark Atlanta University, GA, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zou
authors.affiliation: Center for Cancer Research and Therapeutic Development, Clark Atlanta University, GA, USA.
authors.forename: Dhanushka
authors.initials: D
authors.lastname: Hewa Bostanthirige
authors.affiliation: College of Pharmacy, Mercer University, Atlanta, GA, USA.
authors.forename: Yamini
authors.initials: Y
authors.lastname: Gorantla
authors.affiliation: Center for Cancer Research and Therapeutic Development, Clark Atlanta University, GA, USA.
authors.forename: Peri
authors.initials: P
authors.lastname: Nagappan
authors.affiliation: Center for Cancer Research and Therapeutic Development, Clark Atlanta University, GA, USA.
authors.forename: Shravan Kumar
authors.initials: SK
authors.lastname: Komaragiri
authors.affiliation: Department of Biological Sciences, Border Biomedical Research Center, University of Texas at El Paso, TX, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Sivils
authors.affiliation: College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Xie
authors.affiliation: College of Pharmacy, Mercer University, Atlanta, GA, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Palaniappan
authors.affiliation: Department of Chemistry, RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, USA.
authors.forename: Guangdi
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences, Border Biomedical Research Center, University of Texas at El Paso, TX, USA.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Cox
authors.affiliation: Center for Cancer Research and Therapeutic Development, Clark Atlanta University, GA, USA.
authors.forename: Jaideep
authors.initials: J
authors.lastname: Chaudhary
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003510:Cyclohexanes / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism*; D008297:Male; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism; D010641:Phenotype; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D003510:Cyclohexanes; D055551:HSP27 Heat-Shock Proteins; C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; C000611744:N-(2,3-dichlorophenyl)cyclohexanecarboxamide; D009363:Neoplasm Proteins; D011944:Receptors, Androgen; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4
keywords: 
  HLH
  ; 
  PSA
  ; FKBP51; FKBP52; Hsp27; Hsp90; ID4; MJC13; androgen receptor; castration-resistant; prostate cancer