哺乳动物Sir2蛋白家族成员6 (SIRT6) 调节着一系列重要的生物过程，长期以来被认为与癌症的进展有关。然而，SIRT6在肿瘤发生中的调控机制尚不清楚。本文报告了非小细胞肺癌 (NSCLC) 中SIRT6的肿瘤抑制功能是由乙酰化调控的。具体来说，首次男性缺失基因(MOF)在K128、K160和K267位点乙酰化SIRT6，导致SIRT6去乙酰化酶活性下降，NSCLC中SIRT6的肿瘤抑制功能减弱。在机制上，MOF介导的SIRT6乙酰化妨碍了SIRT6与转录因子FOXA2之间的相互作用，进而导致ZEB2的转录激活，从而促进NSCLC的进展。综上所述，这些数据揭示了在NSCLC中调节SIRT6肿瘤抑制功能的一个乙酰化依赖机制。我们的发现表明，MOF-SIRT6-ZEB2轴可能是NSCLC管理的一个有前途的治疗靶点。本研究结果受版权保护 © 2023 The Authors. 由Elsevier公司出版。保留所有权利。

Mammalian sirtuin 6 (SIRT6) regulates a spectrum of vital biological processes and has long been implicated in the progression of cancer. However, the mechanisms underlying the regulation of SIRT6 in tumorigenesis remain elusive. Here, we report that the tumor-suppressive function of SIRT6 in non-small cell lung cancer (NSCLC) is regulated by acetylation. Specifically, males absent on the first (MOF) acetylates SIRT6 at K128, K160, and K267, resulting in a decreased deacetylase activity of SIRT6 and attenuated SIRT6 tumor-suppressive function in NSCLC. Mechanistically, MOF-mediated SIRT6 acetylation hinders the interaction between SIRT6 and transcriptional factor FOXA2, which in turn leads to the transcriptional activation of ZEB2, thus promoting NSCLC progression. Collectively, these data indicate an acetylation-dependent mechanism that modulates SIRT6 tumor-suppressive function in NSCLC. Our findings suggest that the MOF-SIRT6-ZEB2 axis may represent a promising therapeutic target for the management of NSCLC.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.