Key Laboratory of Medical Epigenetics and Metabolism, Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nature. 2018 Jul;559(7715):637-641. doi: 10.1038/s41586-018-0350-5. Epub 2018 Jul 18.
Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications. Epidemiological studies have suggested that diabetes is also linked to an increased risk of cancer. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype. Here we show that hyperglycaemic conditions have an adverse effect on the DNA 5-hydroxymethylome. We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo. Treatment with the anti-diabetic drug metformin protects AMPK-mediated phosphorylation of serine 99, thereby increasing TET2 stability and 5hmC levels. These findings define a novel 'phospho-switch' that regulates TET2 stability and a regulatory pathway that links glucose and AMPK to TET2 and 5hmC, which connects diabetes to cancer. Our data also unravel an epigenetic pathway by which metformin mediates tumour suppression. Thus, this study presents a new model for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a potential strategy for cancer prevention and treatment.
糖尿病是一种复杂的代谢综合征，其特征是长期的高血糖水平，并经常伴有危及生命的并发症。流行病学研究表明，糖尿病也与癌症风险增加有关。高血糖水平可能是导致糖尿病和癌症之间关联的一个主要因素，但人们对这种关联的分子基础以及高血糖状态如何导致遗传和/或表观遗传改变从而导致癌症表型知之甚少。在这里，我们表明高血糖状态对 DNA 5-羟甲基组有不利影响。我们确定抑癌基因 TET2 是 AMP 激活的蛋白激酶（AMPK）的底物，AMPK 在丝氨酸 99 位磷酸化 TET2，从而稳定肿瘤抑制因子。葡萄糖水平升高会阻碍 AMPK 介导的丝氨酸 99 位磷酸化，导致 TET2 不稳定，随后体外和体内 5-羟甲基胞嘧啶（5hmC）和 TET2 的肿瘤抑制功能失调。抗糖尿病药物二甲双胍可保护 AMPK 介导的丝氨酸 99 位磷酸化，从而增加 TET2 的稳定性和 5hmC 水平。这些发现定义了一种新的“磷酸化开关”，可调节 TET2 的稳定性以及将葡萄糖和 AMPK 与 TET2 和 5hmC 联系起来的调节途径，从而将糖尿病与癌症联系起来。我们的数据还揭示了一种表观遗传途径，二甲双胍通过该途径介导肿瘤抑制。因此，本研究提出了一种新的模型，即恶劣的环境如何直接将表观基因组重新编程为致癌状态，为癌症的预防和治疗提供了一种潜在策略。
