MECHANISTIC CHARACTERIZATION OF THE TUMOR SUPPRESSIVE ROLE OF TIP60 IN CANCER

Abstract

TIP60 is a member of the MYST family of acetyltransferases and is a haploinsufficient tumor suppressor. However, the potential mechanisms endowing its tumor suppressor ability remain incompletely understood. Human papillomavirus (HPV) oncoprotein, E6, targets and destabilizes TIP60, while TIP60 transcriptionally represses E6. This study identified TIP60 represses the catalytic subunit of the human telomerase complex, TERT, a key driver for immortalization. TIP60 acetylates Sp1, positive regulator of TERT, at K639 and inhibits Sp1 binding to the TERT promoter. TIP60-mediated growth suppression of HPV-induced cervical cancer is mediated in part due to TERT repression. Colorectal tumors are known to be accelerated by tumor promoting inflammation. A lower TIP60 expression in colorectal cancer cells was observed. TIP60 regulates the inflammatory response pathway in colorectal cancer cell lines suggesting its role in regulating the tumor microenvironment. This part of the study has established the role of TIP60 in inhibiting tumor progression by regulating genes in colorectal cancer through epigenetic pathways.