Sirt1 deacetylates c-Myc and promotes c-Myc/Max association
Sirt1 deacetylates c-Myc and promotes c-Myc/Max association
复制标题
Sirt1 使 c-Myc 去乙酰化并促进 c-Myc/Max 结合
DOI：
10.1016/j.biocel.2011.07.006
复制
发表时间：
2011-11-01
影响因子：
4
通讯作者：
Liang, Chih-Chuan
中科院分区：
文献类型：
--
作者：
Mao, Beibei;Zhao, Guowei;Liang, Chih-Chuan
c-Myc癌蛋白通过控制细胞增殖、凋亡、分化和代谢在多种生物学过程中起关键作用。特别是c-Myc在许多人类癌症中频繁过表达，并广泛参与肿瘤发生。然而，如何翻译后修饰，特别是乙酰化的c-Myc，有助于其在白血病细胞中的活性仍然在很大程度上未知。Sirt 1是一种NAD依赖的III类组蛋白脱乙酰基酶，它通过使包括p53、E2 F1和叉头蛋白在内的几种转录因子脱乙酰基而在肿瘤发生中起着自相矛盾的作用。在这项研究中，我们表明，Sirt 1与c-Myc的C-末端物理相互作用，并在体外和体内使c-Myc脱乙酰化。此外，Sirt 1对c-Myc的脱乙酰化促进了其与Max（其激活所必需的伴侣）的结合，从而促进了hTERT启动子上c-Myc的反式激活活性。最后，通过RNAi或其抑制剂NAM抑制K562细胞中内源性Sirt 1，导致c-Myc靶基因hTERT、cyclinD 2和LDHA的表达总体下降，从而进一步抑制细胞增殖并将细胞周期阻滞在G1/S期。因此，我们的研究结果表明，Sirt 1对c-Myc活性的积极作用，有效地提高c-Myc/Max协会在人白血病细胞系K562，表明Sirt 1在肿瘤发生中的潜在作用。(C)2011爱思唯尔有限公司版权所有。
The c-Myc oncoprotein plays critical roles in multiple biological processes by controlling cell proliferation, apoptosis, differentiation, and metabolism. Especially, c-Myc is frequently overexpressed in many human cancers and widely involved in tumorigenesis. However, how the post-translational modifications, especially acetylation of c-Myc, contribute to its activity in the leukemia cells remains largely unknown. Sirt1, a NAD-dependent class III histone deacetylase, has a paradoxical role in tumorigenesis by deacetylating several transcription factors, including p53, E2F1 and forkhead proteins. In this study, we show that Sirt1 interacts physically with the C-terminus of c-Myc and deacetylates c-Myc both in vitro and in vivo. Moreover, the deacetylation of c-Myc by Sirt1 promotes its association with Max, a partner essential for its activation, thereby facilitating c-Myc transactivation activity on hTERT promoter. Finally, inhibition of endogenous Sirt1 in K562 cells by either RNAi or its inhibitor NAM causes the overall decrease of c-Myc target genes expression, including hTERT, cyclinD2 and LDHA, which further suppress cell proliferation and arrest cell cycle at G1/S phase. Thus, our results demonstrate the positive effect of Sirt1 on c-Myc activity by efficiently enhancing c-Myc/Max association in human leukemia cell line K562, suggesting a potential role of Sirt1 in tumorigenesis. (C) 2011 Elsevier Ltd. All rights reserved.