Abstract
BackgroundNeuronal 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.ResultsWe 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.ConclusionThese studies support coordinated regulation of δ-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression.
Highlights
Neuronal synaptic junction protein δ-catenin (CTNND2) is often overexpressed in prostatic adenocarcinomas but the mechanisms of its activation are unknown
We demonstrated that Hes1 is a transcriptional repressor for δcatenin and regulates δ-catenin expression in human prostate cancer cells and mouse models of prostate tumors by coordinating with transcription activator E2F1
Hes1 inhibits the upregulation of δ-catenin-luciferase activities induced by E2F1 in prostate cancer cells Human δ-catenin promoter region contains multiple potential binding sites for positive or negative regulators revealed by Genomatix program http://www.genomatix. de/[10]
Summary
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 Hes, 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. Δ-catenin was found to be overexpressed in several cancers of peripheral tissues, including prostate, esophagus, and breast tumors [5], and upregulated in the majority of prostatic adenocarcinomas [6]. Increased expression of δ-catenin disrupts cell-cell junctions [3,6] and promotes human prostate cancer cell growth and tumor progression, altering cell cycle and survival gene profiles [8]
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