Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells.
Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells.
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DOI：
10.1038/s41419-018-1065-0
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发表时间：
2018-09-24
影响因子：
9
通讯作者：
Biroccio A
中科院分区：
文献类型：
--
作者：
Iachettini S;Trisciuoglio D;Rotili D;Lucidi A;Salvati E;Zizza P;Di Leo L;Del Bufalo D;Ciriolo MR;Leonetti C;Steegborn C;Mai A;Rizzo A;Biroccio A
Sirtuin 6(SIRT6)是NAD+依赖的III类脱乙酰基酶sirtuin家族的成员之一，它通过控制转录、基因组稳定性、端粒完整性、DNA修复和自噬在癌症中发挥关键作用。在这里，我们分析了第一个合成的SIRT6激活剂UBCS039的分子和生物学效应。我们的数据表明，UBCS039诱导了几种人类肿瘤细胞系的自噬激活，这一激活依赖于时间，通过蛋白质印迹法检测脂化形式的LC3B的含量，以及通过GFP-LC3的显微镜分析来评估自噬体点的含量。由于催化突变体H133Y不能激活自噬，因此UBCS039介导的自噬激活严格依赖于SIRT6去乙酰化活性。在分子水平上，SIRT6介导的自噬是由ROS水平升高触发的，进而导致AMPK-ULK1-mTOR信号通路的激活。有趣的是，抗氧化剂能够完全抵消UBCS039诱导的自噬，这表明ROS猝发在导致自噬承诺的上游事件中起着关键作用。最后，SIRT6的持续激活导致自噬相关的细胞死亡，这一过程被PAN caspase抑制剂(zVAD-fmk)或自噬抑制剂(CQ)显著减弱。总体而言，我们的结果确定UBCS039是一个有效的SIRT6激活剂，从而提供了一个原理证据，即酶的调节可以通过促进自噬依赖的细胞死亡来影响治疗策略。
Sirtuin 6 (SIRT6) is a member of the NAD+-dependent class III deacetylase sirtuin family, which plays a key role in cancer by controlling transcription, genome stability, telomere integrity, DNA repair, and autophagy. Here we analyzed the molecular and biological effects of UBCS039, the first synthetic SIRT6 activator. Our data demonstrated that UBCS039 induced a time-dependent activation of autophagy in several human tumor cell lines, as evaluated by increased content of the lipidated form of LC3B by western blot and of autophagosomal puncta by microscopy analysis of GFP-LC3. UBCS039-mediated activation of autophagy was strictly dependent on SIRT6 deacetylating activity since the catalytic mutant H133Y failed to activate autophagy. At the molecular level, SIRT6-mediated autophagy was triggered by an increase of ROS levels, which, in turn, resulted in the activation of the AMPK-ULK1-mTOR signaling pathway. Interestingly, antioxidants were able to completely counteract UBCS039-induced autophagy, suggesting that ROS burst had a key role in upstream events leading to autophagy commitment. Finally, sustained activation of SIRT6 resulted in autophagy-related cell death, a process that was markedly attenuated using either a pan caspases inhibitor (zVAD-fmk) or an autophagy inhibitor (CQ). Overall, our results identified UBCS039 as an efficient SIRT6 activator, thereby providing a proof of principle that modulation of the enzyme can influence therapeutic strategy by enhancing autophagy-dependent cell death.
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影响因子：
64.5
作者：
Kugel S;Sebastián C;Fitamant J;Ross KN;Saha SK;Jain E;Gladden A;Arora KS;Kato Y;Rivera MN;Ramaswamy S;Sadreyev RI;Goren A;Deshpande V;Bardeesy N;Mostoslavsky R
通讯作者：
Mostoslavsky R
影响因子：
64.5
作者：
Kawahara TL;Michishita E;Adler AS;Damian M;Berber E;Lin M;McCord RA;Ongaigui KC;Boxer LD;Chang HY;Chua KF
通讯作者：
Chua KF
影响因子：
2.9
作者：
Liu, Wenguang;Wu, Manwu;Li, Jie
通讯作者：
Li, Jie
DOI：
10.1073/pnas.0712145105
发表时间：
2008-03-04
影响因子：
11.1
作者：
Lee, In Hye;Cao, Liu;Finkel, Toren
通讯作者：
Finkel, Toren
影响因子：
19
作者：
Imai, Shin-ichiro;Guarente, Leonard
通讯作者：
Guarente, Leonard