title: Epithelial Hic-5/ARA55 expression contributes to prostate tumorigenesis and castrate responsiveness.
abstract: 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.
authors.affiliation: The Vanderbilt-Ingram Cancer Center and Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Martinez-Ferrer
authors.forename: V
authors.initials: V
authors.lastname: Botta
authors.forename: C
authors.initials: C
authors.lastname: Uwamariya
authors.forename: J
authors.initials: J
authors.lastname: Banerjee
authors.forename: N A
authors.initials: NA
authors.lastname: Bhowmick
mesh_terms: 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
chemical_list: 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
references.citation: Neoplasia. 2010 May;12(5):415-24
references.pmid: 20454513
references.citation: Clin Cancer Res. 2003 Oct 15;9(13):4792-801
references.pmid: 14581350
references.citation: J Biol Chem. 1999 Mar 19;274(12):8316-21
references.pmid: 10075738
references.citation: Sci STKE. 2005 Feb 15;2005(271):cm1
references.pmid: 15713948
references.citation: Science. 2004 Feb 6;303(5659):848-51
references.pmid: 14764882
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12182-7
references.pmid: 18723679
references.citation: Cancer Res. 2006 Jul 15;66(14):7326-33
references.pmid: 16849583
references.citation: Science. 1998 Sep 4;281(5382):1509-12
references.pmid: 9727977
references.citation: Cancer Invest. 2007 Feb;25(1):32-7
references.pmid: 17364555
references.citation: Curr Cancer Drug Targets. 2008 Sep;8(6):490-7
references.pmid: 18781895
references.citation: Mol Carcinog. 2000 Mar;27(3):177-83
references.pmid: 10708479
references.citation: Cancer Res. 2000 Sep 1;60(17):4709-13
references.pmid: 10987273
references.citation: Prostate. 2007 Nov 1;67(15):1664-76
references.pmid: 17854058
references.citation: Oncogene. 2008 Nov 20;27(54):6791-805
references.pmid: 18762808
references.citation: Anticancer Res. 2000 Jan-Feb;20(1A):417-22
references.pmid: 10769689
references.citation: Mol Endocrinol. 1989 Oct;3(10):1515-22
references.pmid: 2608047
references.citation: Cancer Res. 1991 Jul 15;51(14):3753-61
references.pmid: 1712249
references.citation: J Cell Biochem. 2004 Feb 15;91(3):633-45
references.pmid: 14755691
references.citation: Cancer Res. 2005 Jun 15;65(12):5153-62
references.pmid: 15958559
references.citation: J Cell Physiol. 2007 Jun;211(3):736-47
references.pmid: 17299801
references.citation: Cancer Res. 2008 Feb 1;68(3):918-26
references.pmid: 18245495
references.citation: CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
references.pmid: 19474385
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15085-90
references.pmid: 17015840
references.citation: Steroids. 2007 Feb;72(2):218-20
references.pmid: 17166536
references.citation: BMC Cell Biol. 2008 Jan 24;9:4
references.pmid: 18218096
references.citation: Int J Biochem Cell Biol. 2007;39(11):1987-94
references.pmid: 17719831
references.citation: Br J Cancer. 1994 Jan;69(1):130-4
references.pmid: 8286194
references.citation: Urology. 2001 Aug;58(2):289-94
references.pmid: 11489729
references.citation: Oncogene. 2002 Dec 5;21(55):8453-69
references.pmid: 12466965
references.citation: Eur J Pharmacol. 2009 Jan 5;602(1):8-14
references.pmid: 19026633
references.citation: J Biol Chem. 2006 Jan 20;281(3):1755-64
references.pmid: 16291758
references.citation: Cancer Res. 2008 Jun 15;68(12):4709-18
references.pmid: 18559517
references.citation: Cell Death Differ. 2001 Feb;8(2):192-200
references.pmid: 11313721
references.citation: Int J Exp Pathol. 2005 Aug;86(4):219-29
references.pmid: 16045544
references.citation: Differentiation. 2008 Jul;76(6):578-86
references.pmid: 18557761
references.citation: Prostate. 2003 Aug 1;56(3):192-200
references.pmid: 12772188
references.citation: Prostate. 2006 Sep 1;66(12):1329-38
references.pmid: 16835890
references.citation: Mod Pathol. 2008 Sep;21(9):1156-67
references.pmid: 18567993
references.citation: J Biol Chem. 2005 Feb 18;280(7):5154-62
references.pmid: 15561701
references.citation: Cancer Res. 1999 Mar 15;59(6):1366-71
references.pmid: 10096572
references.citation: Anticancer Res. 1997 May-Jun;17(3C):1849-60
references.pmid: 9216635
references.citation: Oncogene. 2008 Nov 27;27(56):7118-30
references.pmid: 18724388
references.citation: Prostate. 2008 Feb 15;68(3):287-95
references.pmid: 18163430
references.citation: Prostate. 2003 Sep 1;56(4):280-6
references.pmid: 12858356
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5124-9
references.pmid: 12700349
references.citation: J Cell Sci. 1999 Jan;112 ( Pt 2):181-90
references.pmid: 9858471
references.citation: Oncogene. 2003 Aug 28;22(36):5602-13
references.pmid: 12944908
references.citation: Cancer Res. 2008 Dec 1;68(23):9918-27
references.pmid: 19047173
references.citation: J Biol Chem. 1994 Oct 28;269(43):26767-74
references.pmid: 7929412
references.citation: Genes Dev. 2005 Feb 1;19(3):362-75
references.pmid: 15687259
references.citation: J Urol. 1983 Jan;129(1):171-4
references.pmid: 6827678
references.citation: J Urol. 2005 Jan;173(1):10-20
references.pmid: 15592017
references.citation: J Cell Biochem. 2004 Jul 1;92(4):810-9
references.pmid: 15211577