Unveiling the methionine cycle: a key metabolic signature and NR4A2 as a methionine-responsive oncogene in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with notable metabolic reprogramming, yet the pivotal metabolic feature driving ESCC progression remains elusive. Here, we show that methionine cycle exhibits robust activation in ESCC and is reversely associated with patient survival. ESCC cells readily harness exogenous methionine to generate S-adenosyl-methionine (SAM), thus promoting cell proliferation. Mechanistically, methionine augments METTL3-mediated RNA m6A methylation through SAM and revises gene expression. Integrative omics analysis highlights the potent influence of methionine/SAM on NR4A2 expression in a tumor-specific manner, mediated by the IGF2BP2-dependent stabilization of methylated NR4A2 mRNA. We demonstrate that NR4A2 facilitates ESCC growth and negatively impacts patient survival. We further identify celecoxib as an effective inhibitor of NR4A2, offering promise as a new anti-ESCC agent. In summary, our findings underscore the active methionine cycle as a critical metabolic characteristic in ESCC, and pinpoint NR4A2 as a novel methionine-responsive oncogene, thereby presenting a compelling target potentially superior to methionine restriction. © The Author(s) 2024.

Authors
Jin X. , Liu L. , Liu D. , Wu J. , Wang C. , Wang S. , Wang F. , Yu G. , Jin X. , Xue Y.-W. , Jiang D. , Ni Y. , Yang X. , Wang M.-S. , Wang Z.-W. , Orlov Y.L. , Jia W. , Melino G. , Liu J.-B. , Chen W.-L.
Journal
Cell death and differentiation
Publisher
Nature Publishing Group
Number of issue
5
Language
English
Pages
558-573
Status
Published
Link
External link
DOI
10.1038/S41418-024-01285-7
Volume
31
Year
2024
Organizations
  • 1 Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
  • 2 Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, Shanghai, 200032, China
  • 3 Department of Thoracic Surgery, The Affiliated Tumor Hospital of Nantong University, Nantong, 226300, China
  • 4 School of Medicine, Southeast University, Nanjing, 210009, China
  • 5 Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
  • 6 Laboratory of Digital Health and Artificial Intelligence, Zhejiang Digital Content Research Institute, Shaoxing, 312000, China
  • 7 Department of Pathology, The Affiliated Tumor Hospital of Nantong University, Nantong, 226300, China
  • 8 Pathology department, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
  • 9 The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310029, China
  • 10 Department of Oncology, Shanxi Provincial Hospital of Traditional Chinese Medicine, Shanxi, 030001, China
  • 11 Department of Thoracic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
  • 12 Department of Breast, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
  • 13 The Digital Health Institute, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russian Federation
  • 14 Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
  • 15 Life Sciences Department, Novosibirsk State University, Novosibirsk, 630090, Russian Federation
  • 16 Institute of Life Sciences and Biomedicine, Far Eastern Federal University, Vladivostok, 690922, Russian Federation
  • 17 Agrarian and Technological Institute, Peoples’ Friendship University of Russia, Moscow, 117198, Russian Federation
  • 18 Department of Pharmacology and Pharmacy, Faculty of Medicine, University of Hong Kong, Hong Kong
  • 19 Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, 00133, Italy
  • 20 Cancer Institute, The Affiliated Tumor Hospital of Nantong University, Nantong, 226361, China
Keywords
Animals; Cell Line, Tumor; Cell Proliferation; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Gene Expression Regulation, Neoplastic; Humans; Methionine; Mice; Mice, Nude; Nuclear Receptor Subfamily 4, Group A, Member 2; Oncogenes; ademetionine; celecoxib; messenger RNA; methionine; nuclear receptor related factor 1; somatomedin B; nuclear receptor related factor 1; animal experiment; animal model; Article; cancer growth; cancer survival; cell proliferation; clinical article; cohort analysis; controlled study; esophageal squamous cell carcinoma; esophageal squamous cell carcinoma cell line; gene expression; human; human cell; human tissue; metabolic parameters; mouse; multiomics; nonhuman; NR4A2 gene; oncogene; pathogenesis; RNA methylation; transcription initiation; animal; drug effect; esophageal squamous cell carcinoma; esophagus tumor; gene expression regulation; genetics; metabolism; nude mouse; oncogene; pathology; tumor cell line
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