Research output: Contribution to journal › Article › peer-review
Unveiling the methionine cycle: a key metabolic signature and NR4A2 as a methionine-responsive oncogene in esophageal squamous cell carcinoma. / Jin, Xing; Liu, Lei; Liu, Dan et al.
In: Cell Death and Differentiation, Vol. 31, No. 5, 05.2024, p. 558-573.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Unveiling the methionine cycle: a key metabolic signature and NR4A2 as a methionine-responsive oncogene in esophageal squamous cell carcinoma
AU - Jin, Xing
AU - Liu, Lei
AU - Liu, Dan
AU - Wu, Jia
AU - Wang, Congcong
AU - Wang, Siliang
AU - Wang, Fengying
AU - Yu, Guanzhen
AU - Jin, Xiaoxia
AU - Xue, Yu Wen
AU - Jiang, Dan
AU - Ni, Yan
AU - Yang, Xi
AU - Wang, Ming Song
AU - Wang, Zhi Wei
AU - Orlov, Yuriy L.
AU - Jia, Wei
AU - Melino, Gerry
AU - Liu, Ji Bin
AU - Chen, Wen Lian
N1 - This work was supported by the National Key R&D Program of China (2023YFC3503200, 2023YFC3503201, 2022YFC3500200, 2022YFC3500202), National Natural Science Foundation of China (31970708, 82002953, 32170778, 82004177, 82072567), Shanghai Frontier Research Base of Disease and Syndrome Biology of Inflammatory cancer transformation (2021KJ03-12), National Scientific and Technological Major Special Project of China (2019ZX09201004-002-013), Tracking Program for Eastern Scholar at Shanghai Institutions of Higher Learning, Shanghai High-level Talent Leadership Program of Traditional Chinese Medicine [ZY(2021-2023)-0403], Scientific Research Project of Industry Development Center of Shanghai University of Traditional Chinese Medicine (602076D), the grant from Nantong Health Commission (MA2021024), Shanghai “Science and Technology Innovation Action Plan” Medical Innovation Research Project-Shanghai Clinical Research Center of Traditional Chinese Medicine Oncology (21MC1930500), Shanghai 13th Five-Year Plan Key Specialty of Traditional Chinese Medicine Oncology (shslczdzk03701), Three-year Action Plan for Shanghai TCM Development and Inheritance Program [ZY(2021-2023)-0401], and Health Commission of Pudong New Area Health and Family Planning Scientific Research Project (PW2019E-1).
PY - 2024/5
Y1 - 2024/5
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Mice
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Esophageal Neoplasms/metabolism
KW - Esophageal Squamous Cell Carcinoma/metabolism
KW - Gene Expression Regulation, Neoplastic
KW - Methionine/metabolism
KW - Mice, Nude
KW - Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism
KW - Oncogenes
UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85189340150&origin=inward&txGid=7ad617efb6bd4d9bd856fbd36ab28b1f
UR - https://www.mendeley.com/catalogue/06875dcb-e745-3556-9fc2-d3b9190dca05/
U2 - 10.1038/s41418-024-01285-7
DO - 10.1038/s41418-024-01285-7
M3 - Article
C2 - 38570607
VL - 31
SP - 558
EP - 573
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1476-5403
IS - 5
ER -
ID: 60553461