TIP60 inhibits metastasis by ablating DNMT1-SNAIL2-driven epithelial-mesenchymal transition program

Yanzhou Zhang; Vanitha Krishna Subbaiah; Deepa Rajagopalan; Cheng Yong Tham; Lissa Nurrul Abdullah; Tan Boon Toh; Min Gong; Tuan Zea Tan; Shweta Pradip Jadhav; Amit Kumar Pandey; Neerja Karnani; Edward Kai-Hua Chow; Jean Paul Thiery; Sudhakar Jha

doi:10.1093/jmcb/mjw038

TIP60 inhibits metastasis by ablating DNMT1-SNAIL2-driven epithelial-mesenchymal transition program

J Mol Cell Biol. 2016 Oct 1;8(5):384-399. doi: 10.1093/jmcb/mjw038.

Authors

Yanzhou Zhang¹, Vanitha Krishna Subbaiah¹, Deepa Rajagopalan^{1

2}, Cheng Yong Tham^{1

2}, Lissa Nurrul Abdullah¹, Tan Boon Toh¹, Min Gong³, Tuan Zea Tan¹, Shweta Pradip Jadhav¹, Amit Kumar Pandey¹, Neerja Karnani^{2

3}, Edward Kai-Hua Chow^{1

4}, Jean Paul Thiery^{1

2

5}, Sudhakar Jha^{1

2}

Affiliations

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

PMID: 27651430
DOI: 10.1093/jmcb/mjw038

Abstract

HIV-Tat-interacting protein of 60 kDa (TIP60) is a lysine acetyltransferase and known to be downregulated in multiple 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 SNAIL2 targets 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.