A crucial role of SUMOylation in modulating Sirt6 deacetylation of H3 at lysine 56 and its tumor suppressive activity
A crucial role of SUMOylation in modulating Sirt6 deacetylation of H3 at lysine 56 and its tumor suppressive activity
复制标题
SUMOylation 在调节 Sirt6 H3 赖氨酸 56 处脱乙酰化及其肿瘤抑制活性中的关键作用
作者：
Cai, J.;Zuo, Y.;Mu, J.
Sirt6是一种具有NAD（+）依赖性活性的组蛋白去乙酰化酶。Sirt6部分通过抑制c-Myc靶基因的表达和核糖体的生物发生而被证明是肿瘤抑制因子。然而，如何调节Sirt6活性在很大程度上是未知的。在这项研究中，我们发现Sirt6可以被小的泛素样修饰剂修饰。Sirt6 SUMOylation缺陷在体内特异性地降低了H3K56的去乙酰化，而不是H3K9。在机制上，我们发现SUMOylation缺陷减少了Sirt6与c-Myc的结合，减少了Sirt6在c-Myc靶基因位点上的占用。因此，Sirt6 SUMOylation缺陷降低了其对H3k56的去乙酰化和对c-Myc靶基因的抑制。此外，Sirt6 SUMOylation缺陷降低了其对细胞增殖和肿瘤发生的抑制作用。因此，这些结果表明SUMOylation在调控H3K56上Sirt6去乙酰化及其肿瘤抑制活性中具有重要作用。
Sirt6 is a histone deacetylase with NAD(+)-dependent activity. Sirt6 has been shown as a tumor suppressor partially via inhibiting the expression of c-Myc target genes and ribosome biogenesis. However, how to regulate Sirt6 activity is largely unknown. In this study, we identify that Sirt6 can be modified by small ubiquitin-like modifier. Sirt6 SUMOylation deficiency specifically decreases its deacetylation of H3K56 but not H3K9 in vivo. Mechanistically, we find that SUMOylation deficiency decreases Sirt6 binding with c-Myc, decreasing Sirt6 occupancy on the locus of c-Myc target genes. Therefore, Sirt6 SUMOylation deficiency reduces its deacetylation of H3k56 and its repression of c-Myc target genes. Moreover, Sirt6 SUMOylation deficiency reduces its suppression of cell proliferation and tumorigenesis. Thus, these results reveal that SUMOylation has an important role in regulation of Sirt6 deacetylation on H3K56, as well as its tumor suppressive activity.