がん研セミナー(7月26日)のお知らせ

演題：The Glucose/AMPK/TET2/5hmC axis constitutes a new pathway linking diabetes to cancer

演者：Yujiang Geno Shi博士 (Division of Endocrinology, Diabetes and Hypertension Brigham and Women’s Hospital and Harvard Medical School)

抄録：Diabetes is a complex metabolic syndrome characterized by prolonged high blood glucose levels and frequently associated with serious life-threatening complications1-3. Epidemiological studies have suggested that diabetes is also linked to elevated risk of developing various cancers4-6. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer. However, little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations, eventually resulting in a cancer phenotype. Here, we show that hyperglycemic conditions have adverse impact on the DNA 5-hydroxymethylome, an epigenetic cancer barrier7. We identify the tumor suppressor TET2 as a novel substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99 (S99), thereby stabilizing the tumor suppressor. Elevated glucose level impedes AMPK-mediated phosphorylation at S99. This results in the destabilization of TET2 followed by dysregulation of both the 5-hydroxymethylcytosine (5hmC) and the tumor suppressive function of TET2 in vitro and in vivo. Treatment with metformin, an anti-diabetic drug, protects AMPK-mediated S99 phosphorylation, thereby increasing TET2 stability and 5hmC levels. These findings define a novel “phospho-switch” that regulates TET2 stability and illustrate a new epigenetic circuit, the glucose/AMPK/TET2/5hmC axis, which links diabetes to cancer. Our data also unravels, for the first time, an epigenetic pathway by which metformin mediates tumor suppression. Thus, this study presents a new paradigm for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a new strategy for cancer prevention and treatment. 

日時：２０１８年７月２６日（木）　１５：００〜

場所：吉田講堂

連絡先：斉藤 典子（５４７４）

＊外部の研究者のご来聴を歓迎いたします。尚、本セミナーの内容は専門的であり、医学・生物分野の研究に携わる方を対象としております