NNMT-DNMT1 Axis is Essential for Maintaining Cancer Cell Sensitivity to Oxidative Phosphorylation Inhibition.
NNMT-DNMT1 Axis is Essential for Maintaining Cancer Cell Sensitivity to Oxidative Phosphorylation Inhibition.
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NNMT–DNMT1 轴对于维持癌细胞对氧化磷酸化抑制的敏感性至关重要
DOI：
10.1002/advs.202202642
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发表时间：
2022-11-16
期刊：
影响因子：
15.1
通讯作者：
Shi, Yufeng
中科院分区：
文献类型：
--
作者：
Wu, Changqing;Liu, Yu'e;Liu, Wenju;Zou, Tianhui;Lu, Shaojuan;Zhu, Chengjie;He, Le;Chen, Jie;Fang, Lan;Zou, Lin;Wang, Ping;Fan, Lihong;Wang, Hongxiang;You, Han;Chen, Juxiang;Fang, Jing-Yuan;Jiang, Cizhong;Shi, Yufeng
关键词：
缺乏对决定癌细胞对氧化磷酸化（OXPHOS）抑制敏感性的分子机制的清晰理解，限制了OXPHOS靶向癌症治疗的发展。在此，通过筛选鉴定对OXPHOS抑制敏感或抗性的癌细胞系。OXPHOS抑制敏感性癌细胞具有增加的OXPHOS活性和沉默的烟酰胺N-甲基转移酶（NNMT）表达。NNMT表达与OXPHOS抑制敏感性负相关，并在功能上下调S-腺苷甲硫氨酸（SAM）的细胞内水平。DNA甲基转移酶1（DNMT 1）的表达，SAM消费者，与OXPHOS抑制敏感性呈正相关。NNMT过表达和DNMT 1抑制使OXPHOS抑制敏感性癌细胞耐药。重要的是，OXPHOS抑制剂（Gboxin和黄连素）的治疗通过抑制OXPHOS敏感但不耐药的癌细胞来阻碍小鼠肿瘤异种移植物的生长。更重要的是，对来自临床试验的62个肿瘤样本的回顾性研究表明，黄连素的施用降低了NNMTlow/DNMT 1high的肿瘤复发率，但对NNMThigh/DNMT 1 low结直肠腺瘤（CRA）没有影响。因此，这些结果揭示了NNMT-DNMT 1轴在确定癌细胞对线粒体OXPHOS的依赖性方面的关键作用，并表明NNMT和DNMT 1是OXPHOS靶向癌症治疗的可靠生物标志物。线粒体氧化磷酸化（OXPHOS）是一个很有前途的肿瘤治疗靶点。NNMT-DNMT 1轴在维持癌细胞对OXPHOS抑制的敏感性方面起着至关重要的作用，NNMT和DNMT 1基因的状态是OXPHOS靶向癌症治疗的可靠生物标志物。
Lacking a clear understanding of the molecular mechanism determining cancer cell sensitivity to oxidative phosphorylation (OXPHOS) inhibition limits the development of OXPHOS‐targeting cancer treatment. Here, cancer cell lines sensitive or resistant to OXPHOS inhibition are identified by screening. OXPHOS inhibition‐sensitive cancer cells possess increased OXPHOS activity and silenced nicotinamide N‐methyltransferase (NNMT) expression. NNMT expression negatively correlates with OXPHOS inhibition sensitivity and functionally downregulates the intracellular levels of S‐adenosyl methionine (SAM). Expression of DNA methyltransferase 1 (DNMT1), a SAM consumer, positively correlates with OXPHOS inhibition sensitivity. NNMT overexpression and DNMT1 inhibition render OXPHOS inhibition‐sensitive cancer cells resistant. Importantly, treatments of OXPHOS inhibitors (Gboxin and Berberine) hamper the growth of mouse tumor xenografts by OXPHOS inhibition sensitive but not resistant cancer cells. What's more, the retrospective study of 62 tumor samples from a clinical trial demonstrates that administration of Berberine reduces the tumor recurrence rate of NNMTlow/DNMT1high but not NNMThigh/DNMT1low colorectal adenomas (CRAs). These results thus reveal a critical role of the NNMT‐DNMT1 axis in determining cancer cell reliance on mitochondrial OXPHOS and suggest that NNMT and DNMT1 are faithful biomarkers for OXPHOS‐targeting cancer therapies. The mitochondrial oxidative phosphorylation (OXPHOS) is a promising target for cancer treatment. NNMT‐DNMT1 axis plays an essential role in maintaining cancer cell sensitivity to OXPHOS inhibition, and the statuses of NNMT and DNMT1 genes are faithful biomarkers for OXPHOS‐targeting cancer therapies.
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