The histone deacetylase SIRT6, a novel tumor suppressor that regulates cancer cell metabolism

CARLOS SEBASTIÁN; LEI ZHONG; AGUSTINA DURSO; DEBORAH TOIBER; D.M. SILBERMAN; JEAN-PIERRE ETCHEGARAY; BÁRBARA MARTÍNEZ-PASTOR; CLAUDIA COSENTINO; SOFIA GIACOSA; JESSICA TRUELOVE; ALEX GUIMARAES; RAUL MOSTOSLAVSKY

Banff, Alberta

Simposio; Keystone Symposia of Cancer and Metabolism; 2012

SIRT6 is a member of a highly conserved family of NAD+‐dependent deacetylasesinvolved in metabolism, stress resistance and life span. SIRT6 deficient mice and cellshave increased genomic instability including chromosomal breaks and translocaDons(Mostoslavsky et al., 2006). In addiDon, SIRT6 deficiency causes metabolic defects invivo, including severe hypoglycemia (Mostoslavsky et al., 2006). Recent data generatedin our laboratory have shown that SIRT6 deficiency leads to increased glucose uptake invitro and in vivo. SIRT6 acts as a H3K9 deacetylase to control the expression of manyglycolyDc genes by acDng as a corepressor of the transcripDon factor Hif1α (Zhong et al.,2010). Thus, SIRT6 regulates genomic stability and aerobic glycolysis, key features oftumor cells. Therefore, it is expected that SIRT6 deficiency will lead to tumors. Here, weshow that SIRT6 defciency promotes transformaDon of mouse embryonic fribroblasts byswitching their metabolism towards aerobic glycolysis. Moreover, knock‐down ofpyruvayte dehydrogenase kinase (PDK1) abrogates the tumorigenic properDes of SIRT6KO MEFs. Finally, we present some data showing decreased expression of SIRT6 inseveral human cancers supporDng a role of SIRT6 as a tumor suppresor.