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- Title
Silencing of the Tropomyosin-1 gene by DNA methylation alters tumor suppressor function of TGF-beta.
- Authors
Varga, Andrea E; Stourman, Nina V; Zheng, Qiao; Safina, Alfiya F; Quan, Lei; Li, Xiurong; Sossey-Alaoui, Khalid; Bakin, Andrei V
- Abstract
Loss of actin stress fibers has been associated with cell transformation and metastasis. TGF-beta induction of stress fibers in epithelial cells requires high molecular weight tropomyosins encoded by TPM1 and TPM2 genes. Here, we investigated the mechanism underlying the failure of TGF-beta to induce stress fibers and inhibit cell migration in metastatic cells. RT-PCR analysis in carcinoma cell lines revealed a significant reduction in TPM1 transcripts in metastatic MDA-MB-231, MDA-MB-435 and SW620 cell lines. Treatment of these cells with demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) increased mRNA levels of TPM1 with no effect on TPM2. Importantly, 5-aza-dC treatment of MDA-MB-231 cells restored TGF-beta induction of TPM1 and formation of stress fibers. Forced expression of TPM1 by using Tet-Off system increased stress fibers in MDA-MB-231 cells and reduced cell migration. A potential CpG island spanning the TPM1 proximal promoter, exon 1, and the beginning of intron 1 was identified. Bisulfite sequencing showed significant cytosine methylation in metastatic cell lines that correlated with a reduced expression of TPM1. Together these results suggest that epigenetic suppression of TPM1 may alter TGF-beta tumor suppressor function and contribute to metastatic properties of tumor cells.
- Publication
Oncogene, 2005, Vol 24, Issue 32, p5043
- ISSN
0950-9232
- Publication type
Journal Article
- DOI
10.1038/sj.onc.1208688