Science Translational Medicine. 10(452):, AUGUST 01, 2018
Issn Print: 1946-6234
Publication Date: August 01, 2018
From diabetes to cancer: Glucose makes the difference
Department of Pathology & Laboratory Medicine, Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Email: email@example.comEpidemiological studies suggest that there is a strong link between diabetes and cancer. However, the casual relationship between the two remains unclear, as does any underlying molecular mechanism by which diabetes could potentially contribute to cancer. Considering roughly 10% of the U.S population has diabetes, it is important to address these questions, which may help provide important prophylactic treatment to prevent the development of cancer in this population.Ten-eleven translocation 2 (TET2) is an enzyme that catalyzes the conversion of DNA methylation (5mC) to hydroxymethylation (5hmC), wherein low 5hmC contributes to tumorigenesis. By comparing 5hmC levels between healthy donors and patients with diabetes, Wu et al. found that diabetic patients displayed lower 5hmC levels compared with healthy donors. Upon treating glucose-responsive cells with high glucose, TET2 was found to be depleted at the protein level. As AMPK is the key energy sensor regulated by glucose availability and there are two putative AMPK kinase substrate motifs found in TET2, the authors pursued a potential effect of high glucose on TET2 phosphorylation. They found that high glucose inhibited AMPK activity, which led to decreased TET2 phosphorylation and reduced TET2 protein stability in melanoma cells. Therefore, patients with diabetes may display decreased TET2 and diminished 5hmC, and potentially be susceptible to tumor formation. By treating melanoma cells with AMPK activators such as metformin (a first-line medication for the treatment of type 2 diabetes), TET2 became stabilized followed by increased 5hmC and enhanced tumor suppression.Overall, this important research provides a strong mechanistic connection between diabetes and cancer. Further investigation should be carried out to understand how other factors in TET2 enzymatic reactions, such as oxygen level and α-ketoglutarate, may play a role regulating TET2 activity in conjunction with or independent of glucose level. In addition, it is important to identify the specific target genes of TET2 in melanoma cells that may be responsible for its glucose-driven phenotype. Lastly, it also remains to be determined whether this is a general mechanism for other cancers besides melanoma and breast cancer as shown in this study.
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