Dataset Information

Silencing DNA methyltransferase 1 (DNMT1) inhibits proliferation, metastasis and invasion in ESCC by suppressing methylation of RASSF1A and DAPK.

ABSTRACT: Our previous study showed DNMT1 is up-regulated in esophageal squamous cell carcinoma (ESCC), which is associated with methylation of tumor suppressors. In the current study, we investigate the role of DNMT1 in ESCC. We found silencing DNMT1 inhibited proliferation, metastasis and invasion of three different ESCC cells, K150, K410 and K450. We also found silencing DNMT1 induced G1 arrest and cell apoptosis in K150, K410 and K450 cells. In vivo study showed silencing DNMT1 suppressed tumor growth in nude mice. In addition, silencing DNMT1 increased expression of tumor suppressor genes, RASSF1A and DAPK, in ESCC cells and ESCC xenograft in nude mice. Moreover, silencing DNMT1 decreased methylation in promoter of RASSF1A and DAPK. In conclusion, our data demonstrated that silencing DNMT1 inhibits proliferation, metastasis and invasion in ESCC by suppressing methylation of RASSF1A and DAPK.

SUBMITTER: Bai J

PROVIDER: S-EPMC5190084 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Silencing DNA methyltransferase 1 (DNMT1) inhibits proliferation, metastasis and invasion in ESCC by suppressing methylation of RASSF1A and DAPK.

Bai Jian J Zhang Xue X Hu Kai K Liu Bangqing B Wang Haiyong H Li Angui A Lin Feng F Zhang Lifei L Sun Xiaolin X Du Zhenzong Z Song Jianfei J

Oncotarget 20160701 28

Our previous study showed DNMT1 is up-regulated in esophageal squamous cell carcinoma (ESCC), which is associated with methylation of tumor suppressors. In the current study, we investigate the role of DNMT1 in ESCC. We found silencing DNMT1 inhibited proliferation, metastasis and invasion of three different ESCC cells, K150, K410 and K450. We also found silencing DNMT1 induced G1 arrest and cell apoptosis in K150, K410 and K450 cells. In vivo study showed silencing DNMT1 suppressed tumor growth ...[more]

PMID: 27286455

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Project description:The heterogeneous breast cancers can be classified into different subtypes according to their histopathological characteristics and molecular signatures. Foxa1 expression is linked with luminal breast cancer (LBC) with good prognosis, whereas Twist1 expression is associated with basal-like breast cancer (BLBC) with poor prognosis owing to its role in promoting epithelial-to-mesenchymal transition (EMT), invasiveness and metastasis. However, the regulatory and functional relationships between Twist1 and Foxa1 in breast cancer progression are unknown. In this study, we demonstrate that in the estrogen receptor (ERα)-positive LBC cells Twist1 silences Foxa1 expression, which has an essential role in relieving Foxa1-arrested migration, invasion and metastasis of breast cancer cells. Mechanistically, Twist1 binds to Foxa1 proximal promoter and recruits the NuRD transcriptional repressor complex to de-acetylate H3K9 and repress RNA polymerase II recruitment. Twist1 also silences Foxa1 promoter by inhibiting AP-1 recruitment. Twist1 expression in MCF7 cells silenced Foxa1 expression, which was concurrent with the induction of EMT, migration, invasion and metastasis of these cells. Importantly, restored Foxa1 expression in these cells largely inhibited Twist1-promoted migration, invasion and metastasis. Restored Foxa1 expression did not change the Twist1-induced mesenchymal cellular morphology and the expression of Twist1-regulated E-cadherin, β-catenin, vimentin and Slug, but it partially rescued Twist1-silenced ERα and cytokeratin 8 expression and reduced Twist1-induced integrin α5, integrin β1 and MMP9 expression. In a xenografted mouse model, restored Foxa1 also increased Twist1-repressed LBC markers and decreased Twist1-induced BLBC markers. Furthermore, Twist1 expression is negatively correlated with Foxa1 in the human breast tumors. The tumors with high Twist1 and low Foxa1 expressions are associated with poor distant metastasis-free survival. These results demonstrate that Twist1's silencing effect on Foxa1 expression is largely responsible for Twist1-induced migration, invasion and metastasis, but less responsible for Twist1-induced mesenchymal morphogenesis and expression of certain EMT markers.

Dataset Information

Silencing DNA methyltransferase 1 (DNMT1) inhibits proliferation, metastasis and invasion in ESCC by suppressing methylation of RASSF1A and DAPK.

Publications

Silencing DNA methyltransferase 1 (DNMT1) inhibits proliferation, metastasis and invasion in ESCC by suppressing methylation of RASSF1A and DAPK.

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