期刊
NUCLEIC ACIDS RESEARCH
卷 46, 期 18, 页码 9456-9470出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gky659
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资金
- National Research Foundation Singapore
- Singapore Ministry of Education under its Research Centers of Excellence initiative to the Cancer Science Institute of Singapore [R-713-006-014-271]
- National Medical Research Council [NMRC] [CBRG-NIG BNIG11nov001]
- Ministry of Education Academic Research Fund [MOE AcRF Tier 1] [T1-2012 Oct-04, T1-2016 Apr-01]
- RNA Biology Center at CSI Singapore
- NUS
- Singapore Ministry of Education's Tier 3 grants [MOE2014-T3-1-006]
- Yong Loo Lin School of Medicine, National University of Singapore
- Cancer Science Institute of Singapore
- Yong Loo Lin School of Medicine
- National University of Singapore
- French Ministry for Europe and Foreign Affairs
- French Ministry for Higher Education, Research and Innovation
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 retro-transposon 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.
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