MULTIPLE ENZYMATIC FUNCTIONS OF SIRT2 AND ITS INVOLVEMENT IN CANCER
SIRT2 belongs to the mammalian sirtuin or NAD-dependent lysine deacylase family. Growing evidence suggests that SIRT2 plays important roles in cell cycle regulation, stress response, metabolism and differentiation by deacetylating a wide variety of substrates. Targeting SIRT2 for cancer treatment has been a topic of debate due to conflicting reports and lack of potent and specific inhibitors. I began the project with the development and mechanistic study of SIRT2 inhibitors. From a collection of mechanism-based small molecule inhibitors mimicking different lysine acyl modifications, I characterized that a thiomyristoyl lysine compound (TM), a potent SIRT2-specific inhibitor, has broad anticancer effect in various human cancer cells and mouse models of breast cancer. Mechanistically, I demonstrated that SIRT2 inhibition promotes c-Myc ubiquitination and degradation and that the anticancer effect of TM correlates with its ability to decrease c-Myc level. This study suggests that SIRT2 inhibition could be utilized to target c-Myc and that potent and selective SIRT2 inhibitors are promising anticancer agents. SIRT2 has been reported to have lysine defatty-acylase activity in addition to the previously known deacetylase activity. However, whether the defatty-acylase activity is physiologically relevant has not been investigated. I identified the oncoprotein K-Ras4a as a SIRT2 defatty-acylase substrate. I further elucidated that SIRT2-mediated lysine defatty-acylation promotes endomembrane localizaiton of K-Ras4a, enhances its interaction with A-Raf, and thus promotes cellular transformation. This study not only highlights lysine fatty acylation as a previously unknown regulatory mechanism for the Ras family of GTPases that is distinct from cysteine fatty acylation, but also unveils a new mechanism by which SIRT2 is involved in cancer by defatty-acylating K-Ras4a. This finding also provides further support that SIRT2 is a promising target for cancer treatment.
c-Myc; K-Ras; Lysine fatty acylation; SIRT2; Sirtuin; Chemistry; cancer
Cerione, Richard A.; Weiss, Robert S.
Chemistry and Chemical Biology
Ph. D., Chemistry and Chemical Biology
Doctor of Philosophy
Attribution-NonCommercial-NoDerivatives 4.0 International
dissertation or thesis
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