title: TIP60 inhibits metastasis by ablating DNMT1-SNAIL2-driven epithelial-mesenchymal transition program.
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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Yanzhou
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Vanitha Krishna
authors.initials: VK
authors.lastname: Subbaiah
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore,Singapore.
authors.forename: Deepa
authors.initials: D
authors.lastname: Rajagopalan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore,Singapore.
authors.forename: Cheng Yong
authors.initials: CY
authors.lastname: Tham
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Lissa Nurrul
authors.initials: LN
authors.lastname: Abdullah
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Tan Boon
authors.initials: TB
authors.lastname: Toh
authors.affiliation: Singapore Institute for Clinical Sciences, A* STAR, National University of Singapore, Singapore.
authors.forename: Min
authors.initials: M
authors.lastname: Gong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Tuan Zea
authors.initials: TZ
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Shweta Pradip
authors.initials: SP
authors.lastname: Jadhav
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Pandey
authors.affiliation: Department 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.
authors.forename: Neerja
authors.initials: N
authors.lastname: Karnani
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Edward Kai-Hua
authors.initials: EK
authors.lastname: Chow
authors.affiliation: Cancer 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.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore,Singapore.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Jha
keywords: DNA methylation; DNMT1; EpCAM; SNAIL2; TIP60; epithelial-mesenchymal transition