Exploring the Roles of the Histone Deacetylase and Longevity Factor SIRT6 in Cancer.

Abstract

Identification of pathways that regulate longevity in an evolutionarily conserved manner is a major focus of modern biogerontology. Interest in the sirtuin family of deacetylases/ADP-ribosyltransferases/deacylases began with the observation that increased expression of SIR2 extends replicative lifespan in budding yeast. The seven mammalian sirtuin homologs have been the focus of intense investigation for their potential impacts on health- and lifespan. My thesis work focuses specifically on the mammalian sirtuin SIRT6. SIRT6 plays multiple roles in metabolic homeostasis and genome integrity through modification of histones and other protein targets; consequently SIRT6 suppresses many age-associated pathologies such as neoplasia, cardiac hypertrophy, and glucose intolerance. SIRT6 overexpression results in extended lifespan in male mice, suggesting that SIRT6 may represent a true functional ortholog of yeast SIR2, and supporting an evolutionarily conserved role for sirtuins in longevity. In this work, we identified a protective role for SIRT6 in suppressing tumorigenesis. First, SIRT6 suppresses aerobic glycolysis, the preferred form of energy metabolism in cancer cells, by inhibiting the expression of various glycolytic proteins. Second, SIRT6 regulates cell growth by reducing ribosomal biogenesis via the proto-oncogene c-MYC. Additionally, we identified H3K56ac, a histone mark involved in DNA repair which is often elevated in cancer, as a novel target for SIRT6 and we identified an increased incidence of aneuploidy in SIRT6-deficient cells. Thus, SIRT6’s role in maintaining genomic integrity could possibly provide a third means through which SIRT6 suppresses tumor development. Conversely, examination of established cancer cell lines and tissues, revealed high SIRT6 protein expression and cytoplasmic localization. However, SIRT6 activity appears to be compromised as SIRT6 no longer acts upon its target H3K56. Overall, the identified tumor suppressive properties of SIRT6 are possibly the underlying mechanism through which SIRT6 extends mammalian lifespan, and provides therapeutic potential for the treatment of various malignancies.