Cai J, Zuo Y, Wang T, Cao Y, Cai R, Chen F-L, Cheng J, Mu J
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Third People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Oncogene. 2016 Sep 15;35(37):4949-56. doi: 10.1038/onc.2016.24. Epub 2016 Feb 22.
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.
Sirt6是一种具有NAD(+)依赖性活性的组蛋白脱乙酰酶。Sirt6已被证明是一种肿瘤抑制因子，部分原因是它能抑制c-Myc靶基因的表达和核糖体生物合成。然而，如何调节Sirt6的活性在很大程度上尚不清楚。在本研究中，我们发现Sirt6可以被小泛素样修饰物修饰。Sirt6的SUMO化缺陷在体内特异性地降低了其对H3K56的去乙酰化作用，但对H3K9没有影响。从机制上讲，我们发现SUMO化缺陷会降低Sirt6与c-Myc的结合，减少Sirt6在c-Myc靶基因位点上的占据。因此，Sirt6的SUMO化缺陷会降低其对H3K56的去乙酰化作用及其对c-Myc靶基因的抑制作用。此外，Sirt6的SUMO化缺陷会降低其对细胞增殖和肿瘤发生的抑制作用。因此，这些结果表明SUMO化在调节Sirt6对H3K56的去乙酰化作用及其肿瘤抑制活性方面具有重要作用。
