Id-1 promotes TGF-β1-induced cell motility through MEK-ERK-mediated HSP27 activation in prostate epithelial cells

Abstract

Id-1 (inhibitor of differentiation or DNA binding-1) gene encodes a helix-loop helix protein which dimerizes and blocks the basic HLH protein from binding DNA. It has been positively associated with cell proliferation, cell cycle progression, and invasiveness during tumorigenesis. In addition, Id-1 has been shown to modulate cellular sensitivity to transforming growth factor β1 (TGF-β1). Here we demonstrate a critical role of Id-1 in promoting TGF-β1-induced cell motility in a non-malignant prostate epithelial cell line, NPTX cells. We found that ectopic Id-1 expression promoted F-actin stress fiber formation which was associated with increased cell-substrate adhesion, in TGF-β1-treated cells. This process was mediated through activation of MEK-ERK signaling pathway and subsequent activation of heat shock protein 27 (Hsp27). In addition, our results also indicated that Id-1 overexpression led to disruption of the adherens junction complex at cell-cell contacts through down-regulation of E-cadherin and redistribution of cellular localization of β-catenin, along with up-regulation of N-cadherin in the TGF-β1-treated cells. These lines of evidence reveal a novel tumor promoting role of Id-1 through reorganization of actin cytoskeleton and disassembly of cell-cell adhesion in response to TGF-β1 in human prostate epithelial cells and suggest that intracellular Id-1 levels might be a determining factor for switching TGF-β1 from a growth inhibitor to a tumor promoter during prostate carcinogenesis. [Supported by RGC grants (HKU7478/03M) to XHW and YCW (HKU7490.03M, 7470/04M, NSFC/RGC N_HKU738/03, HKU Foundation Seed Fund, 03)].