期刊
CANCER LETTERS
卷 544, 期 -, 页码 -出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2022.215803
关键词
EEF1AKMT3; Protein methylation; TP53; Gastric tumor; Tumor suppressor
类别
资金
- Basic Science Research Program through the National Research Foundation of Korea (NRF)
- Ministry of Science and ICT, Republic of Korea [2017R1A6A1A03015642, 2020R1F1A1073219]
- Ministry of Health and Welfare
- National Research Foundation of Korea [2020R1F1A1073219] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The study explored the pathological role of a nonhistone methyltransferase in gastric cancer (GC), identified EEF1AKMT3 as a novel tumor suppressive methyltransferase, and revealed its mechanism of action through regulating the methylation of MAP2K7 and the degradation of TP53. The findings suggest potential targeted therapy in GC by manipulating the dysregulated EEF1AKMT3/MAP2K7/TP53 signaling axis.
The importance of methylation in the tumorigenic responses of nonhistone proteins, such as TP53, PTEN, RB1, AKT, and STAT3, has been emphasized in numerous studies. In parallel, the corresponding nonhistone protein methyltransferases have been acknowledged in the pathophysiology of cancer. Thus, this study aimed to explore the pathological role of a nonhistone methyltransferase in gastric cancer (GC), identify nonhistone substrate protein, and understand the underlying mechanism. Interestingly, among the 24 methyltransferases and methyltransferase family 16 (MTF16) proteins, EEF1AKMT3 (METTL21B) expression was prominently lower in GC tissues than in normal adjacent tissues and was associated with a worse prognosis. In addition, EEF1AKMT3knockdown induced gastric tumor invasiveness and migration. Through gain and loss-of-function studies, mass spectrometry analysis, RNA-seq, and phospho-antibody array, we identified EEF1AKMT3 as a novel tumor suppressive methyltransferase that catalyzes the monomethylation of MAP2K7 (MKK7) at K296, thereby decreasing the phosphorylation, ubiquitination, and degradation of TP53. Furthermore, EEF1AKMT3, pMAP2K7, and TP53 protein levels were positively correlated in GC tissues. Collectively, our results delineate the tumor-suppressive function of the EEF1AKMT3/MAP2K7/TP53 signaling axis and suggest the dysregulation of the signaling axis as potential targeted therapy in GC.
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