Smad signaling is required to maintain epigenetic silencing during breast cancer progression.
Smad signaling is required to maintain epigenetic silencing during breast cancer progression.
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DOI：
10.1158/0008-5472.can-09-1872
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发表时间：
2010-02-01
期刊：
影响因子：
11.2
通讯作者：
Thiagalingam S
中科院分区：
文献类型：
--
作者：
Papageorgis P;Lambert AW;Ozturk S;Gao F;Pan H;Manne U;Alekseyev YO;Thiagalingam A;Abdolmaleky HM;Lenburg M;Thiagalingam S
Aberrant regulatory DNA methylation patterns have been associated with breast cancer progression. While most efforts have been focused on describing the gene targets for DNA methylation, the molecular events that define the activity of the DNA methylation machinery have remained elusive. Here we describe the use of a breast cancer cell line model system to investigate the mechanisms that regulate epigenetic alterations of gene expression patterns responsible for epithelial-mesenchymal transition (EMT), a critical step during conversion to malignant breast cancer. We found that breast cancer cells which have undergone EMT exhibit overactive TGFβ signaling and loss of expression of genes including CDH1, CGN, CLDN4 and KLK10 mediated by DNA hypermethylation of their corresponding promoter regions. Consistent with the notion that activated TGFβ-Smad signaling is involved in “epigenetic memory” to maintain epigenetically silenced state of critical genes, disruption of Smad signaling due to Smad7 overexpression or depletion of Smad2, but not Smad4, in mesenchymal-like breast cancer cells resulted in DNA demethylation and re-expression of the corresponding genes. This reversal of epigenetic changes was accompanied with the acquisition of epithelial morphology and suppression of invasive properties of breast cancer cells. Furthermore, disruption of TGFβ signaling caused a corresponding decrease in DNMT1 binding activity suggesting that failure to maintain methylation of the newly synthesized DNA is the likely cause of demethylation. In summary, our studies reveal for the first time, that hyperactive TGFβ-TGFβR-Smad2 signaling axis is involved in the maintenance of epigenetic silencing of critical target genes to facilitate breast cancer progression.
