Aberrant transforming growth factor-beta 1 signaling and SMAD4 nuclear translocation confer epigenetic repression of ADAM19 in ovarian cancer

Michael Chan, Yi-Wen Huang, Corinna Hartman-Frey, Chieh-Ti Kuo, Daniel Deatherage, Huaxia Qin, Alfred S Cheng, Pearlly S Yan, Ramana V Davuluri, Tim H Huang, Kenneth Nephew and Huey-Jen L Lin

Year 2008, Volume 10, Issue 9

Abstract

Transforming Growth Factor-beta (TGF-£])/SMAD signaling is a key growth regulatory pathway often dysregulated in ovarian cancer and other malignancies. Although loss of TGF-£]-mediated growth inhibition has been shown to contribute to aberrant cell behavior, the epigenetic consequence(s) of impaired TGF-£]/SMAD signaling on target genes is not well established. In this study, we show that TGF-£]1 causes growth inhibition of normal ovarian surface epithelial cells, induction of the nuclear translocation SMAD4, and upregulation of the ADAM19 (a disintegrin and metalloprotease domain 19), a newly identified TGF-£]1 target gene. Conversely, induction and nuclear translocation of SMAD4 was negligible in ovarian cancer cells refractory to TGF-£]1 stimulation, and ADAM19 expression was greatly reduced. Furthermore, in the TGF-£]1 refractory cells, an inactive chromatin environment, marked by repressive histone modifications (trimethyl-H3K27 and dimethyl-H3K9) as well as histone deacetylase, was associated with the ADAM19 promoter region. However, the CpG island found within the promoter and first exon of ADAM19 remained generally unmethylated. Although disrupted growth factor signaling has been linked to epigenetic gene silencing in cancer, this is the first evidence demonstrating that impaired TGF-£]1 signaling can result in the formation of a repressive chromatin state and epigenetic suppression of ADAM19. Given the emerging role of ADAMs family proteins in growth factor regulation in normal cells, we suggest that epigenetic dysregulation of ADAM19 may contribute to the neoplastic process in ovarian cancer.

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