Deacetylase-independent function of SIRT6 couples GATA4 transcription factor and epigenetic activation against cardiomyocyte apoptosis. Issue 9 (2nd April 2020)

• Record Type: Journal Article
• Authors: Peng, Linyuan; Qian, Minxian; Liu, Zuojun; Tang, Xiaolong; Sun, Jie; Jiang, Yue; Sun, Shimin; Cao, Xinyue; Pang, Qiuxiang; Liu, Baohua
• Is Part Of: Nucleic acids research. Volume 48:Issue 9(2020)
• Page Start: 4992
• Page End: 5005
• Publication Date: 2020-04-02
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkaa214
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: SIRT6 deacetylase activity improves stress resistance via gene silencing and genome maintenance. Here, we reveal a deacetylase-independent function of SIRT6, which promotes anti-apoptotic gene expression via the transcription factor GATA4. SIRT6 recruits TIP60 acetyltransferase to acetylate GATA4 at K328/330, thus enhancing its chromatin binding capacity. In turn, GATA4 inhibits the deacetylase activity of SIRT6, thus ensuring the local chromatin accessibility via TIP60-promoted H3K9 acetylation. Significantly, the treatment of doxorubicin (DOX), an anti-cancer chemotherapeutic, impairs the SIRT6–TIP60–GATA4 trimeric complex, blocking GATA4 acetylation and causing cardiomyocyte apoptosis. While GATA4 hyperacetylation-mimic retains the protective effect against DOX, the hypoacetylation-mimic loses such ability. Thus, the data reveal a novel SIRT6–TIP60–GATA4 axis, which promotes the anti-apoptotic pathway to prevent DOX toxicity. Targeting the trimeric complex constitutes a new strategy to improve the safety of DOX chemotherapy in clinical application.