Deacetylase-independent function of SIRT6 couples GATA4 transcription factor and epigenetic activation against cardiomyocyte apoptosis
Open Access
- 2 April 2020
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 48 (9), 4992-5005
- https://doi.org/10.1093/nar/gkaa214
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.Funding Information
- National Natural Science Foundation of China (91849208, 91949124, 81871114, 81571374, 81972602, 81702909)
- National Key Research and Development Program of China (2017YFA0503900)
- Science and Technology Program of Guangdong Province in China (2014A030308011, 2017B030301016, 2019A1515010472, 2019B030301009)
- Shenzhen Government (ZDSYS20190902093401689, KQJSCX20180328093403969, JCYJ20180507182044945)
This publication has 62 references indexed in Scilit:
- Identification of the molecular basis of doxorubicin-induced cardiotoxicityNature Medicine, 2012
- H3K9 and H3K14 acetylation co-occur at many gene regulatory elements, while H3K14ac marks a subset of inactive inducible promoters in mouse embryonic stem cellsBMC Genomics, 2012
- 6-alkylsalicylates are selective Tip60 inhibitors and target the acetyl-CoA binding siteEuropean Journal of Medicinal Chemistry, 2012
- Mechanism of anthracycline-mediated down-regulation of GATA4 in the heartCardiovascular Research, 2010
- Virtual Ligand Screening of the p300/CBP Histone Acetyltransferase: Identification of a Selective Small Molecule InhibitorCell Chemical Biology, 2010
- SIRT1 Regulates Autoacetylation and Histone Acetyltransferase Activity of TIP60*Online Journal of Public Health Informatics, 2010
- Functional dissection of SIRT6: Identification of domains that regulate histone deacetylase activity and chromatin localizationMechanisms of Ageing and Development, 2010
- The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1αCell, 2010
- Transcription Factor GATA4 Inhibits Doxorubicin-induced Autophagy and Cardiomyocyte DeathOnline Journal of Public Health Informatics, 2010
- SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatinNature, 2008