A novel post-translational modification of SIRT6 regulates its function via modulating its deacetylase activity

Abstract

Silent information regulator proteins (SIRT), or sirtuins, are evolutionarily conserved NAD+- dependent deacetylases. There are seven sirtuins in mammalian have been identified, namely SIRT1-7, with different subcellular localization. SIRT6 is a nuclear sirtuin and has been well defined to play critical roles in diverse biological processes including genome maintenance, metabolism, inflammation, tumor suppression and aging. Despite intensive studies have been done focusing on the targets and signaling networks regulated by SIRT6, our knowledge regarding the regulation of SIRT6 itself remains limited. In this study, we identify that SIRT6 can be post-translationally modified by acetylation. We show that males absent on the first (MOF) is the major acetyltransferase responsible for SIRT6 acetylation. We further show three lysine sites within the core catalytic domain of SIRT6 are targeted by MOF. SIRT6 acetylation does not affect its subcellular localization. However, acetylation of SIRT6 negatively modulates its deacetylase activity towards its histone substrates, H3K9ac and H3K56ac both in vitro and in vivo. As SIRT6 achieves its tumor suppression function partially through its deacetylase activity on histone acetylation marks, the acetylation of SIRT6 may serve as a novel mechanism controlling the tumorigenesis process. Moreover, MOF, the major acetyltransferase of SIRT6, was found to be more frequently overexpressed in human nonsmall cell lung cancer (NSCLC) tissues and high expression of MOF was associated with poor prognosis in patients. Interestingly, SIRT6 function was also found to be compromised in human non-small cell lung cancer tissues and cell lines. Therefore, it is reasonable to speculated that the highly expressed MOF contributes to NSCLC through acetylating and regulating SIRT6 function. Taken together, our results uncover a post-translational mechanism in modulating SIRT6 activity and might provide novel therapeutic strategy in the treatment of lung cancer.