MECHANISM AND IMPLICATIONS OF DESTABILIZING TIP60, A TUMOUR SUPPRESSOR

Abstract

HIV-Tat-interacting protein of 60 KDa(TIP60) is a lysine acetyltransferase and known to be down-regulated in multiple cancers. I have investigated role of TIP60 in virus-induced cancer and breast cancer. In cervical cancers, Human Papillomavirus(HPV) E6-oncoprotein utilizes EDD1/UBR5 to target TIP60 for degradation. Restoring TIP60 levels either by overexpressing TIP60 or depletion of EDD1 in HPV positive cells significantly inhibits colony formation in vitro and tumor growth in vivo. In breast cancer, TIP60 expression abrogates cell migration and metastatic potential. Mechanistically, this is through TIP60’s mediated destabilization of DNMT1. Furthermore, I show that Snail2 recruits DNMT1 to the promoter of epithelial genes, resulting in increased promoter DNA methylation and repression of these genes. In pathophysiological scenario, TIP60 significantly down-regulated 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 cancer progression and stabilization of TIP60 through inhibiting EDD1 could be a promising strategy to treat cancers.