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講演者: Yujiang Geno Shi (Associate Professor, Harvard Medical School)

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

日時: 7月25日(水) 12:00-13:00

会場: 発生医学研究所1階 カンファレンス室



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.



Yujian Geno Shi博士は世界に先駆けてヒストン脱メチル酵素LSD1を発見、当時国際的にも攻めあぐねていたヒストン脱メチル修飾が存在することを示すのみならず、それに続いてJumonji型ヒストン脱メチル酵素やDNA脱メチル酵素TETの相次ぐ同定に繋がるきっかけとなるブレークスルーとなりました。

ヒストン脱メチル酵素発見の経緯や体験談を織り交ぜて、最近の研究内容(Nature, in press)についても紹介していただきます。

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