Autocrine BMP4 signalling regulates ID3 proto-oncogene expression in human ovarian cancer cells

Bone morphogenetic protein (BMP)-4 signalling leads to the direct upregulation of ID3 proto-oncogene expression in human ovarian cancer cells. An upstream BMP4-responsive enhancer element consisting of a palindromic BMP response element (BRE) site and CAGA box was identified similar to 3.0 kb upstream of the human ID3 gene, and a nearly-identical element exists in the second intron of the ID3 gene. BMP4 stimulation leads to the direct binding of Smads 1/5 and Smad4 to the upstream and intronic enhancers, and together both enhancers cooperate to yield heightened BMP4-mediated ID3 promoter activity. We further demonstrate that ID3 is overexpressed in human ovarian cancer cells when compared to normal ovarian surface epithelial cells, and treatment of ovarian cancer cells with the BMP4 antagonist Noggin abrogates endogenous ID3 gene expression. Our findings define the mechanism of BMP4-mediated ID3 gene expression, and support the notion that ovarian cancer cells possess autocrine BMP4 signalling required to sustain ID3 overexpression which may contribute to human ovarian cancer pathogenesis. (c) 2008 Elsevier B.V. All rights reserved.