Rajagopalan D1,2, Tirado-Magallanes R1, Bhatia SS1, Teo WS1, Sian S1, Hora S1,2, Lee KK1, Zhang Y1, Jadhav SP1, Wu Y3, Gan YH2, Karnani N2,3, Benoukraf T1, Jha S1,2.
1 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.
2 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
3 Singapore Institute for Clinical Sciences, A* STAR, Singapore.
TIP60 is a lysine acetyltransferase and is known to be a haplo-insufficient tumor suppressor. TIP60 downregulation is an early event in tumorigenesis which has been observed in several cancer types including breast and colorectal cancers. However, the mechanism by which it regulates tumor progression is not well understood. In this study, we identified the role of TIP60 in the silencing of endogenous retroviral elements (ERVs). TIP60-mediated silencing of ERVs is dependent on BRD4. TIP60 and BRD4 positively regulate the expression of enzymes, SUV39H1 and SETDB1 and thereby, the global H3K9 trimethylation (H3K9me3) level. In colorectal cancer, we found that the loss of TIP60 de-represses retrotransposon elements genome-wide, which in turn activate the cellular response to pathogens, mediated by STING, culminating in an induction of Interferon Regulatory Factor 7 (IRF7) and associated inflammatory response. In summary, this study has identified a unique mechanism of ERV regulation in cancer cells mediated by TIP60 and BRD4 through regulation of histone H3 K9 trimethylation, and a new tumor suppressive role of TIP60 in vivo.