Cutting edge Seminar
Speaker: Yujiang Geno Shi （Associate Professor, Harvard Medical School）
Title: The Glucose/AMPK/TET2/5hmC axis constitutes a new pathway linking diabetes to cancer
Date&Time: 25 Jul. (Wed.) 2018, 12:00- 13:00
Venue: Conference Room(1F), IMEG
Abstract:
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.
The long-term goal of research in Geno Shi Lab is to understand how processing of human genomic information is controlled by epigenetic factors and pathways, and how dysregulation of these epigenetic events contributes to complex human diseases. With a focus on histone demethylation and DNA modifications, Shi lab is mainly interested in defining the fundamental principles of epigenetics and understanding how chromatin modifying enzymes are intrinsically connected to hormone signaling, metabolic states and/or environmental cues that regulate distinct biological and pathological processes. In addition to our mechanism-oriented basic research, there are multiple translational projects that we are currently pursuing including: 1) understanding how histone and DNA demethylases regulate the crosstalk between tumors and the immune system and how their inhibition can be integrated into cancer immunotherapy 2) deciphering how obesity and diabetes through a new environmental-to-chromatin signaling axis to directly program or reprogram an epigenome, linking these metabolic syndromes to life-threatening complications 3) characterizing histone modification and DNA methylation aberrancies in neurological disorders/diseases such as in Alzheimer’s disease and Major Depressive Disorders (MDD), and dissecting the role of these modifications in disease initiation and progression.
石黒 内6606, ishiguro@kumamoto-u.ac.jp
