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Sirtuin deacetylase and RAS-dependent cancers

Institution: Beckman Research Institute of the City of Hope
Investigator(s): Wenyong Chen, Ph.D.
Award Cycle: 2011 (Cycle 20) Grant #: 20XT-0121 Award: $420,000
Subject Area: Cancer
Award Type: Exploratory/Developmental Award
Abstracts

Initial Award Abstract
SIRT1 is an enzyme that removes the acetyl group from acetylated lysine in a protein, i.e. deacetylation. The deacetylation reaction results in positive charges on lysine residues on a protein. SIRT1 plays important roles for promoting mammalian cell survival under many physical, metabolic and environmental stresses. SIRT1 protein is over-produced in many human cancers, but its roles in cancer are not well defined. By extensive work, my laboratory has recently identified crucial roles of SIRT1 gene expression activated by BCR-ABL, a cancer-causing gene for chronic myelogenous leukemia, for efficient BCR-ABL transformation of normal hematopoietic progenitor cells to leukemic cells and chemoresistance of chronic myelogenous leukemia.

RAS oncogenes are among the most frequently mutated genes in human malignancies, especially in lung, pancreas, colon/intestine, biliary tract and skin cancers. Tobacco smoking increases or is associated with mutations of RAS oncogenes in lung cancer. Mutant RAS-driven cancers are highly chemoresistant and notoriously difficult to treat. RAS oncoproteins are localized onto cellular membranes for their biological functions through adding a fatty acid chain, a process termed farnesylation; however, pharmacological inhibition of farnesylation is largely ineffective for cancer treatment and molecular mechanism for this failure is not clear. We hypothesize that SIRT1 may have a broad role in oncoprotein-mediated chemoresistance. We have found that SIRT1 is crucial for RAS transformation of normal cells to cancer cells, and that RAS proteins are subjected to modification by lysine acetylation. We propose that SIRT1 may regulate RAS functions by deacetylation resulting in positive charges on RAS protein, which provides an alternative way for RAS activation when farnesylation is blocked. If it proves true, simultaneous blocking RAS deacetylation and farnesylation may dramatically inhibit RAS functions. Since SIRT1 can deacetylate many proteins working on large complexes or on the same networks, we also propose to examine roles of SIRT1 for regulating several mutant KRAS downstream effectors by protein deacetylation. These studies will significantly help us understand how SIRT1 may play specific roles in cancer and how deacetylation may contribute to mutant KRAS oncogenic signaling. Successful completion of proposed studies may have direct implication for improving treatment of RAS-dependent cancers including mutant RAS-bearing lung cancer by combinatory inhibition of SIRT1 deacetylation and RAS farnesylation or RAS downstream effectors.
Publications

Emerging roles of SIRT1 in cancer drug resistance
Periodical: Genes & Cancer Index Medicus:
Authors: Wang Z, Chen WY ART
Yr: 2013 Vol: 4 Nbr: Abs: Pg: 82-90

Roles of SIRT1 in leukemogenesis
Periodical: Current Opinion in Hematology Index Medicus:
Authors: Chen WY, Bhatia R. ART
Yr: 2013 Vol: 20 Nbr: Abs: Pg: 308-313

Sorting out functions of sirtuins in cancer
Periodical: Oncogene Index Medicus:
Authors: Roth M, Chen WY ART
Yr: 2013 Vol: Nbr: Abs: Pg: pmid 23604120