Epithelial Hic-5/ARA55 expression contributes to prostate tumorigenesis and castrate responsiveness.
Stromal-epithelial interactions dictate prostate tumorigenesis and response to castration. Hydrogen peroxide-inducible clone 5 (Hic-5/ARA55) is a transforming growth factor-beta (TGF-β)-induced coactivator of androgen receptor (AR) expressed in the prostate stroma. Interestingly, following castration, we identified epithelial expression of Hic-5/ARA55 in mouse and human prostate tissues. To determine the role of epithelial Hic-5 in prostate cancer progression and castration responsiveness, we compared LNCaP cells having Hic-5 stably expressed with the parental LNCaP cells following tissue recombination xenografts with mouse prostate stromal cells. We previously identified knocking out prostate stromal TGF-β signaling potentiated castrate-resistant prostate tumors, in a Wnt-dependent manner. The LNCaP chimeric tumors containing prostate fibroblasts conditionally knocked out for the TGF-β type II receptor (Tgfbr2-KO) resulted in larger, more invasive, and castration-resistant tumors compared those with floxed (control) stromal cells. However, the LNCaP-Hic5 associated with Tgfbr2-KO fibroblasts generated chimeric tumors with reduced tumor volume, lack of invasion and restored castration dependence. Neutralization of canonical Wnt signaling is shown to reduce prostate tumor size and restore regression following castration. Thus, we hypothesized that epithelial Hic-5/ARA55 expression negatively regulated Wnt signaling. The mechanism of the Hic-5/ARA55 effects on castration was determined by analysis of the c-myc promoter. C-myc luciferase reporter activity suggested Hic-5/ARA55 expression inhibited c-myc activity by β-catenin. Sequential ChIP analysis indicated β-catenin and T-cell-specific 4 (TCF4) bound the endogenous c-myc promoter in the absence of Hic-5 expression. However, the formation of a TCF4/Hic-5 repressor complex inhibited c-myc promoter activity, by excluding β-catenin binding with TCF4 on the promoter. The data indicate Hic-5/ARA55 expression in response to castration-enabled epithelial regression through the repression of c-myc gene at the chromatin level.
Li
X
X
The Vanderbilt-Ingram Cancer Center and Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA.
Martinez-Ferrer
M
M
Botta
V
V
Uwamariya
C
C
Banerjee
J
J
Bhowmick
N A
NA
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016259:Genes, myc; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D060588:LIM Domain Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009919:Orchiectomy; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011944:Receptors, Androgen / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D011944:Receptors, Androgen; D018125:Receptors, Transforming Growth Factor beta; C532096:TCF4 protein, human; C490351:TGFB1I1 protein, human; C090090:Tgfb1i1 protein, mouse; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
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