TIP60 is a lysine acetyltransferase which belongs to the MYST family of acetyltransferases and is known to be a haploinsufficient tumor suppressor. TIP60 downregulation is an early event in tumorigenesis which has been observed in several cancer types including breast and colorectal cancers. Colorectal cancers are characterized by inflammation wherein inflammatory bowel disease greatly increases the risk of colorectal cancer. In this symposium, I will discuss the role of TIP60 in the silencing of endogenous retroviral elements (ERVs). We have identified a unique mechanism of ERV regulation in cancer cells mediated by TIP60 and BRD4 through regulation of Histone H3K9 trimethylation. I will also discuss our efforts to exploit this pathway to sensitize colorectal cancer to reverse transcriptase inhibitors.