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dc.contributor.authorJing, Hui
dc.date.accessioned2018-10-03T19:27:40Z
dc.date.available2019-12-18T07:00:45Z
dc.date.issued2017-12-30
dc.identifier.otherJing_cornellgrad_0058F_10577
dc.identifier.otherhttp://dissertations.umi.com/cornellgrad:10577
dc.identifier.otherbibid: 10474186
dc.identifier.urihttps://hdl.handle.net/1813/59083
dc.description.abstractSIRT2 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.
dc.language.isoen_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectc-Myc
dc.subjectK-Ras
dc.subjectLysine fatty acylation
dc.subjectSIRT2
dc.subjectSirtuin
dc.subjectChemistry
dc.subjectcancer
dc.titleMULTIPLE ENZYMATIC FUNCTIONS OF SIRT2 AND ITS INVOLVEMENT IN CANCER
dc.typedissertation or thesis
thesis.degree.disciplineChemistry and Chemical Biology
thesis.degree.grantorCornell University
thesis.degree.levelDoctor of Philosophy
thesis.degree.namePh. D., Chemistry and Chemical Biology
dc.contributor.chairLin, Hening
dc.contributor.committeeMemberCerione, Richard A.
dc.contributor.committeeMemberWeiss, Robert S.
dcterms.licensehttps://hdl.handle.net/1813/59810
dc.identifier.doihttps://doi.org/10.7298/X4DB800G


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