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  3. Multi-omics analysis reveals NNMT as a master metabolic regulator of metastasis in esophageal squamous cell carcinoma

Multi-omics analysis reveals NNMT as a master metabolic regulator of metastasis in esophageal squamous cell carcinoma

  • NPJ Precis Oncol. 2024 Jan 30;8(1):24. doi: 10.1038/s41698-024-00509-w.
Qi Huang # 1,  Haiming Chen # 2 3,  Dandan Yin # 4,  Jie Wang 5 6 7,  Shaodong Wang 2 3,  Feng Yang 2 3,  Jiawei Li 1,  Teng Mu 1,  Jilun Li 1,  Jia Zhao 1,  Rong Yin 5 6 7,  Wei Li 8,  Mantang Qiu 9 10,  Erbao Zhang 11,  Xiangnan Li 12
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450003, China.
  • 2 Department of Thoracic Surgery, Peking University People's Hospital, Beijing, 100044, China.
  • 3 Thoracic Oncology Institute, Peking University People's Hospital, Beijing, 100044, China.
  • 4 Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Zhong Fu Road, Gulou District, Nanjing, 210003, China.
  • 5 Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital and Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, 21009, China.
  • 6 Department of Science and Technology, Jiangsu Cancer Hospital and Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, 21009, China.
  • 7 Biobank of Lung Cancer, Jiangsu Biobank of Clinical Resources, Nanjing, 21009, China.
  • 8 Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China. liwei_real@126.com.
  • 9 Department of Thoracic Surgery, Peking University People's Hospital, Beijing, 100044, China. qiumantang@163.com.
  • 10 Thoracic Oncology Institute, Peking University People's Hospital, Beijing, 100044, China. qiumantang@163.com.
  • 11 Department of Epidemiology, Center for Global Health, School of Public Health, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China. erbaozhang@njmu.edu.cn.
  • 12 Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450003, China. lxn-2000@163.com.
  • # Contributed equally.
PMID: 38291241 DOI: 10.1038/s41698-024-00509-w
Abstract

Metabolic reprogramming has been observed in Cancer metastasis, whereas metabolic changes required for malignant cells during lymph node metastasis of esophageal squamous cell carcinoma (ESCC) are still poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) of paired ESCC tumor tissues and lymph nodes to uncover the reprogramming of tumor microenvironment (TME) and metabolic pathways. By integrating analyses of scRNA-seq data with metabolomics of ESCC tumor tissues and plasma samples, we found nicotinate and nicotinamide metabolism pathway was dysregulated in ESCC patients with lymph node metastasis (LN+), exhibiting as significantly increased 1-methylnicotinamide (MNA) in both tumors and plasma. Further data indicated high expression of N-methyltransferase (NNMT), which converts active methyl groups from the universal methyl donor, S-adenosylmethionine (SAM), to stable MNA, contributed to the increased MNA in LN+ ESCC. NNMT promotes epithelial-mesenchymal transition (EMT) and metastasis of ESCC in vitro and in vivo by inhibiting E-cadherin expression. Mechanically, high NNMT expression consumed too much active methyl group and decreased H3K4me3 modification at E-cadherin promoter and inhibited m6A modification of E-cadherin mRNA, therefore inhibiting E-cadherin expression at both transcriptional and post-transcriptional level. Finally, a detection method of lymph node metastasis was build based on the dysregulated metabolites, which showed good performance among ESCC patients. For lymph node metastasis of ESCC, this work supports NNMT is a master regulator of the cross-talk between cellular metabolism and epigenetic modifications, which may be a therapeutic target.

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