MOF-mediated acetylation of SIRT6 disrupts SIRT6-FOXA2 interaction and represses SIRT6 tumor-suppressive function by upregulating ZEB2 in NSCLC.

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.