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TIP60 Inhibits Metastasis by Ablating DNMT1-SNAIL2-driven Epithelial-Mesenchymal Transition Program (J Mol Cell Bio, Sep 2016)

Zhang Y1, Subbaiah VK1, Rajagopalan D2, Tham CY2, Abdullah LN1, Toh TB1, Gong M3, Tan TZ1, Jadhav SP1, Pandey AK1, Karnani N4, Chow EK5, Thiery JP6, Jha S7

1Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2Cancer Science Institute of Singapore, National University of Singapore, Singapore Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
3Singapore Institute for Clinical Sciences, A* STAR, National University of Singapore, Singapore.
4Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Singapore Institute for Clinical Sciences, A* STAR, National University of Singapore, Singapore.
5Cancer Science Institute of Singapore, National University of Singapore, Singapore Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
6Cancer Science Institute of Singapore, National University of Singapore, Singapore Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Institute of Molecular and Cell Biology, A*STAR, Singapore.
7Cancer Science Institute of Singapore, National University of Singapore, Singapore Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore csisjha@nus.edu.sg.

Abstract:

HIV-Tat-interacting protein of 60 kDa (TIP60) is a lysine acetyltransferase and known to be downregulated inmultiple cancers. Among various signalling pathways, TIP60 is implicated in regulating epithelial-mesenchymal transition (EMT). Here, we show that TIP60 expression abrogates cell migration and metastatic potential of breast cancer cells using in vitro and in vivo models. Mechanistically, we show that this is through its ability to destabilize DNMT1 and inhibit SNAIL2 function (SNAIL2-mediated EMT/cell migration). Depletion of TIP60 stabilizes DNMT1 and increases SNAIL2 levels, resulting in EMT. Recruitment of DNMT1 to the SNAIL2targets in the absence of TIP60 increases DNA methylation on their promoter region and further represses the expression of epithelial markers. In pathophysiological scenario, we find TIP60 to be significantly downregulated in breast cancer patients with poor overall survival and disease-free survival prognoses. These data suggest that levels of TIP60 can be a prognostic marker of breast cancer progression and stabilization of TIP60 could be a promising strategy to treat cancers.

KEYWORDS: DNA methylation; DNMT1; EpCAM; SNAIL2; TIP60; epithelial−mesenchymal transition

 

PMID: 27651430