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一部のがんで観察されている5hmCの低下は、5mCから5hmCへの変換を触媒する腫瘍抑制因子TET2の活性低下を原因としている。今回の研究で、Yujiang Geno Shiたちは、糖尿病患者における血液細胞の5hmCレベルが低下することを見いだした。また、種々の細胞株を用いた実験から、TET2の安定性と5hmCレベルを調節する、いわゆる「リン酸スイッチ」を同定した。栄養素とエネルギーの重要なセンサーとして働く酵素AMP活性化キナーゼ(AMPK)は、TET2をリン酸化して安定化させる。高血糖状態はAMPKの活性を損なうことが知られており、このためTET2が不安定化して、5hmCレベルの低下につながったと考えられる。


Hyperglycaemic conditions have an adverse impact on levels of 5-hydroxymethylation (5hmC), a DNA modification that can be perturbed in cancer, according to research in Nature this week. The findings could help to explain why observations of diabetes can be linked to increased cancer risk.

Diabetes is a complex metabolic syndrome characterized by prolonged high blood glucose levels and frequently associated with serious and life-threatening complications. Previous epidemiological studies have suggested that diabetes is also linked to elevated risk of cancer development. 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 or epigenetic alterations, eventually causing cancer.

The reduction of 5hmC observed in some cancers is due to diminished activity of the tumour suppressor TET2, which catalyses the conversion of 5mC to 5hmC. Yujiang Geno Shi and colleagues find there are decreased levels of 5hmC in the blood cells of diabetic patients. Turning to experiments in cell lines, they identify a so-called ‘phospho-switch’ that regulates TET2 stability and levels of 5hmC. The enzyme AMP-activated kinase, which serves as a key nutrient and energy sensor, phosphorylates TET2 and stabilises it. Elevated glucose levels, which are known to impede AMPK activity, therefore result in destabilised TET2 and lower levels of 5hmC.

The authors also provide data in mice to suggest that the anti-diabetic drug metformin can inhibit tumour growth via this AMPK-TET2 pathway, providing novel insight for future clinical investigations.

doi: 10.1038/s41586-018-0350-5

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