Deacetylase-independent function of SIRT6 couples GATA4 transcription factor and epigenetic activation against cardiomyocyte apoptosis
Deacetylase-independent function of SIRT6 couples GATA4 transcription factor and epigenetic activation against cardiomyocyte apoptosis
复制标题
SIRT6 的脱乙酰酶独立功能结合 GATA4 转录因子和表观遗传激活对抗心肌细胞凋亡
DOI：
10.1093/nar/gkaa214
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发表时间：
2020-05-21
影响因子：
14.9
通讯作者：
Liu, Baohua
中科院分区：
文献类型：
--
作者：
Peng, Linyuan;Qian, Minxian;Liu, Baohua
SIRT6脱乙酰酶活性通过基因沉默和基因组维持来提高抗逆性。在这里，我们揭示了SIRT6的一个不依赖于脱乙酰酶的功能，它通过转录因子GATA4促进抗凋亡基因的表达。SIRT6在K328/330处招募Tip60乙酰转移酶来乙酰化GATA4，从而增强其染色质结合能力。反过来，GATA4抑制SIRT6的脱乙酰酶活性，从而通过Tip60促进的H3K9乙酰化确保局部染色质的可及性。值得注意的是，抗癌化疗药物阿霉素(DOX)的治疗损害了SIRT6-Tip60-GATA4三聚体复合体，阻断了GATA4的乙酰化，并导致心肌细胞凋亡。当GATA4高乙酰化模拟物保留了对DOX的保护作用时，低乙酰化模拟物失去了这种能力。因此，这些数据揭示了一个新的SIRT6-Tip60-GATA4轴，它促进了抗凋亡途径，以防止DOX毒性。靶向三聚体构成了提高DOX化疗临床应用安全性的新策略。
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 factorGATA4. 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 anticancer 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.