title: Human homolog of Drosophila Hairy and enhancer of split 1, Hes1, negatively regulates δ-catenin (CTNND2) expression in cooperation with E2F1 in prostate cancer.
abstract: BACKGROUND
  Neuronal synaptic junction protein δ-catenin (CTNND2) is often overexpressed in prostatic adenocarcinomas but the mechanisms of its activation are unknown. To address this question, we studied the hypothesis that Hes1, human homolog of Drosophila Hairy and enhancer of split (Hes) 1, is a transcriptional repressor of δ-catenin expression and plays an important role in molecular carcinogenesis.
  
  
  RESULTS
  We identified that, using a δ-catenin promoter reporter assay, Hes1, but not its inactive mutant, significantly repressed the upregulation of δ-catenin-luciferase activities induced by E2F1. Hes1 binds directly to the E-boxes on δ-catenin promoter and can reduce the expression of δ-catenin in prostate cancer cells. In prostate cancer CWR22-Rv1 and PC3 cell lines, which showed distinct δ-catenin overexpression, E2F1 and Hes1 expression pattern was altered. The suppression of Hes1 expression, either by γ-secretase inhibitors or by siRNA against Hes1, increased δ-catenin expression. γ-Secretase inhibition delayed S/G2-phase transition during cell cycle progression and induced cell shape changes to extend cellular processes in prostate cancer cells. In neuroendocrine prostate cancer mouse model derived allograft NE-10 tumors, δ-catenin showed an increased expression while Hes1 expression was diminished. Furthermore, E2F1 transcription was very high in subgroup of NE-10 tumors in which Hes1 still displayed residual expression, while its expression was only moderately increased in NE-10 tumors where Hes1 expression was completely suppressed.
  
  
  CONCLUSIONS
  These studies support coordinated regulation of δ-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression.
authors.affiliation: Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Lu
authors.forename: Jiao
authors.initials: J
authors.lastname: Zhang
authors.forename: Kwonseop
authors.initials: K
authors.lastname: Kim
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Case
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Matusik
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Wolfe
authors.forename: Jongdee
authors.initials: J
authors.lastname: Nopparat
authors.forename: Qun
authors.initials: Q
authors.lastname: Lu
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D051177:Catenins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072056:Transcription Factor HES-1; D000095002:Delta Catenin
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051177:Catenins; D004151:Dipeptides; D050687:E2F1 Transcription Factor; D018398:Homeodomain Proteins; D000072056:Transcription Factor HES-1; D000095002:Delta Catenin; C493753:E2F1 protein, human; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C078493:HES1 protein, human