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Silencing of the Tropomyosin-1 gene by DNA methylation alters tumor suppressor function of TGF-beta.

Authors: Varga, AE  Stourman, NV  Zheng, Q  Safina, AF  Quan, L  Li, X  Sossey-Alaoui, K  Bakin, AV 
Citation: Varga AE, etal., Oncogene. 2005 Jul 28;24(32):5043-52.
Pubmed: (View Article at PubMed) PMID:15897890
DOI: Full-text: DOI:10.1038/sj.onc.1208688

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.


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CRRD Object Information
CRRD ID: 8656006
Created: 2014-05-28
Species: All species
Last Modified: 2014-05-28
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.