Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, P.R. China; School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, P.R. China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, P.R. China.
Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, P.R. China.
Cell Rep. 2023 Aug 29;42(8):112939. doi: 10.1016/j.celrep.2023.112939. Epub 2023 Aug 10.
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.
哺乳动物沉默调节蛋白 6（SIRT6）调节着一系列重要的生物学过程，长期以来一直与癌症的进展有关。然而，SIRT6 在肿瘤发生中的调节机制仍不清楚。在这里，我们报告 SIRT6 在非小细胞肺癌（NSCLC）中的肿瘤抑制功能受乙酰化调控。具体而言，缺失第一男性（MOF）在 K128、K160 和 K267 处乙酰化 SIRT6，导致 SIRT6 的去乙酰化酶活性降低，减弱 SIRT6 在 NSCLC 中的肿瘤抑制功能。在机制上，MOF 介导的 SIRT6 乙酰化阻碍了 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。总之，这些数据表明一种依赖于乙酰化的机制调节 SIRT6 在 NSCLC 中的肿瘤抑制功能。我们的研究结果表明，MOF-SIRT6-ZEB2 轴可能代表 NSCLC 管理的有前途的治疗靶点。
