The EEF1AKMT3/MAP2K7/TP53 axis suppresses tumor invasiveness and metastasis in gastric cancer.

Autor: Hong YH; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Aziz N; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea., Park JG; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea; Division of Translational Science, Research Institute, National Cancer Center, Goyang, 10408, Republic of Korea., Lee D; Department of Surgery, Ajou University School of Medicine, And Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, 16499, Republic of Korea., Kim JK; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea., Kim SA; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea., Choi W; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea., Lee CY; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea., Lee HP; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea., Huyen Trang HT; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea., Kim HG; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea., Jeon YJ; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea., Kim B; PharminoGen, Yongin, 16827, Republic of Korea., Kim Y; PharminoGen, Yongin, 16827, Republic of Korea., Kim KH; Proteomic Analysis Team, Research Institute, National Cancer Center, Goyang, 10408, Republic of Korea., Yoo BC; Division of Translational Science, Research Institute, National Cancer Center, Goyang, 10408, Republic of Korea., Han JW; Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon, 16419, South Korea., Parameswaran N; Department of Physiology and Division of Pathology, Michigan State University, East Lansing, MI, 48824, USA., Kim JH; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea. Electronic address: kjhkjhmlml@skku.edu., Hur H; Department of Surgery, Ajou University School of Medicine, And Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, 16499, Republic of Korea. Electronic address: hhcmc75@naver.com., Cho JY; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea. Electronic address: jaecho@skku.edu.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2022 Sep 28; Vol. 544, pp. 215803. Date of Electronic Publication: 2022 Jun 24.
DOI: 10.1016/j.canlet.2022.215803
Abstrakt: 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, EEF1AKMT3-knockdown 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, p-MAP2K7, 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.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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