<br>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,Advanced Science

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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
Advanced Science ( IF 14.3 ) Pub Date : 2022-11-16 , DOI: 10.1002/advs.202202642
Changqing Wu ₁ , Yu'e Liu ₁ , Wenju Liu ₂ , Tianhui Zou ₃ , Shaojuan Lu ₁ , Chengjie Zhu ₁ , Le He ₁ , Jie Chen ₁ , Lan Fang ₁ , Lin Zou ₄ , Ping Wang ₁ , Lihong Fan ₅ , Hongxiang Wang ₆ , Han You ₇ , Juxiang Chen ₆ , Jing-Yuan Fang ₃ , Cizhong Jiang ₂ , Yufeng Shi _{1,

2,

8}

Affiliation

Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai, 200092, China.
Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
Clinical Research Unit, Children's Hospital of Shanghai Jiaotong University, Shanghai, 200062, China.
Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
Department of Neurosurgery, Changhai Hospital, Naval Medical University, NO.168 Changhai Road, Shanghai, 200433, China.
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361005, China.
Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, 200092, China.

对决定癌细胞对氧化磷酸化 (OXPHOS) 抑制敏感性的分子机制缺乏清晰的了解，限制了 OXPHOS 靶向癌症治疗的发展。在这里，通过筛选鉴定对 OXPHOS 抑制敏感或耐药的癌细胞系。对 OXPHOS 抑制敏感的癌细胞具有增加的 OXPHOS 活性和沉默的烟酰胺N-甲基转移酶 (NNMT) 表达。 NNMT 表达与 OXPHOS 抑制敏感性呈负相关，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 (DNMT1)（一种 SAM 消耗者）的表达与 OXPHOS 抑制敏感性呈正相关。 NNMT 过表达和 DNMT1 抑制使 OXPHOS 抑制敏感的癌细胞产生耐药性。重要的是，OXPHOS 抑制剂（Gboxin 和小檗碱）的治疗通过对 OXPHOS 抑制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。此外，对临床试验中的 62 个肿瘤样本进行的回顾性研究表明，服用小檗碱可降低 NNMT^低/DNMT1^高的肿瘤复发率，但不能降低 NNMT^高/DNMT1^低结直肠腺瘤 (CRA) 的肿瘤复发率。因此，这些结果揭示了 NNMT-DNMT1 轴在确定癌细胞对线粒体 OXPHOS 依赖方面的关键作用，并表明 NNMT 和 DNMT1 是 OXPHOS 靶向癌症治疗的可靠生物标志物。

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NNMT-DNMT1 Axis is Essential for Maintaining Cancer Cell Sensitivity to Oxidative Phosphorylation Inhibition

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 NNMT^low/DNMT1^high but not NNMT^high/DNMT1^low 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.

更新日期：2022-11-16

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