Metformin sensitizes endometrial cancer cells to chemotherapy through IDH1-induced Nrf2 expression via an epigenetic mechanism
Metformin sensitizes endometrial cancer cells to chemotherapy through IDH1-induced Nrf2 expression via an epigenetic mechanism
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二甲双胍通过表观遗传机制通过 IDH1 诱导 Nrf2 表达使子宫内膜癌细胞对化疗敏感
DOI：
10.1038/s41388-018-0360-7
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发表时间：
2018-10-18
期刊：
影响因子：
8
通讯作者：
Zheng, Wenxin
中科院分区：
文献类型：
--
作者：
Bai, Mingzhu;Yang, Linlin;Zheng, Wenxin
化疗耐药性是子宫内膜癌治愈的主要障碍，而二甲双胍已被证明对子宫内膜癌的化疗敏感。一项新发现表明异柠檬酸脱氢酶1（IDH 1）参与癌症化疗耐药性。最近的研究表明，表观遗传修饰促进化疗耐药性。然而，IDH 1是否通过表观遗传修饰在二甲双胍诱导的子宫内膜癌化疗敏感性中发挥作用还不完全清楚。采用免疫组化和Elisa法分别检测子宫内膜组织和血清中IDH 1的表达。进行蛋白质印迹以确定在各种处理后IDH 1-KG-TET 1-Nrf 2信号通路中的关键分子的表达的变化。斑点印迹法用于评估二甲双胍给药或质粒转染后的总体羟甲基化水平。通过荧光素酶测定监测IDH 1启动子区中的抗氧化反应元件（ARE）活性。SRB法检测癌细胞对化疗药物的敏感性。我们发现，IDH 1及其下游介质异常表达导致的子宫内膜癌组织中IDH 1信号通路的激活赋予了化疗耐药性。我们发现二甲双胍治疗可减轻这种作用。斑点印迹和HMeDIP分析显示，二甲双胍阻断了IDH 1-KG-TET 1介导的Nrf 2羟甲基化水平的增强，消除了化疗耐药性。此外，我们观察到，化学抗性通过调节环增强，其中Nrf 2通过结合IDH 1启动子区域中的ARE位点激活IDH 1-KG-TET 1-Nrf 2信号传导。我们的研究结果强调了IDH 1-KG-TET 1-Nrf 2信号传导在化疗耐药性中的关键作用，并表明二甲双胍和化疗药物的合理联合治疗具有抑制化疗耐药性的潜力。
Chemoresistance is the major obstacle to cure endometrial cancer, whereas metformin has demonstrated sensitization to chemotherapy in endometrial cancer. A novel finding states that isocitrate dehydrogenase 1 (IDH1) involves in cancer chemoresistance. Recent studies have revealed that epigenetic modifications facilitate chemoresistance. However, whether IDH1 play a role in metformin-induced endometrial cancer chemosensitivity through epigenetic modification is incompletely understood. Immunohistochemistry and Elisa assays were used to evaluate the expression pattern of IDH1 in endometrial tissue and serum, respectively. Western blot was performed to determine changes in expression of key molecules in the IDH1-ɑ-KG-TET1-Nrf2 signaling pathway after various treatments. Dot blot assays were used to assess global hydroxymethylation levels after metformin administration or plasmid transfection. Antioxidant response element (ARE) activity in the IDH1 promoter region was monitored by luciferase assay. Cancer cell sensitivity to chemotherapy was detected by SRB assay. We found that activation of the IDH1 signaling pathway in endometrial cancer tissue resulting from aberrant expression of IDH1 and its downstream mediators conferred chemoresistance. We found that this effect was abated by metformin treatment. Dot blot and HMeDIP assays revealed that metformin blocked IDH1-ɑ-KG-TET1-mediated enhancement of Nrf2 hydroxymethylation levels, eliminating chemoresistance. Moreover, we observed that chemoresistance was enhanced via a regulatory loop in which Nrf2 activated IDH1-ɑ-KG-TET1-Nrf2 signaling via binding to the ARE sites in the IDH1 promoter region. Our findings highlight a critical role of IDH1-ɑ-KG-TET1-Nrf2 signaling in chemoresistance and suggest that rational combination therapy with metformin and chemotherapeutics has the potential to suppress chemoresistance.