Review

Progress of research on m6A demethylases in gastric cancer

  • Shuang JIANG ,
  • Jiwei YU
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  • Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
YU Jiwei, E-mail: jenniferyu919@126.com.

Received date: 2023-08-21

  Accepted date: 2023-12-11

  Online published: 2024-02-28

Abstract

Gastric cancer (GC) is one of the most common malignancies in the digestive system. Many patients are found in advanced stage and have a poor prognosis. Surgery and chemotherapy remain the main treatments for gastric cancer. N6-methyladenosine (m6A) is a hot topic in tumor research in recent years. As the most common form of RNA modification in eukaryotes, m6A can regulate various stages of the RNA cycle, including RNA splicing, processing, degradation, and translation, thereby regulating RNA expression and function, playing a critical role in various pathways such as cell differentiation, development, and metabolism. The m6A demethylase can remove methyl groups on RNA, ensuring that m6A methylation is a dynamic and reversible process. As a key enzyme in the m6A methylation process, the imbalance of m6A demethylases fat mass and obesity-associated protein (FTO), AlkB homolog 5 (ALKBH5) and ALKBH3 regulate the progression of gastric cancer through various mechanisms, which is closely related to the occurrence and development of gastric cancer. These m6A demethylases regulate the signaling pathway, alter the proliferation and invasion ability of gastric cancer cells, affect its resistance to chemotherapy drugs, participate in regulating the immune response and mitochondrial metabolism of gastric cancer, and affect the growth of gastric cancer cells. They are expected to become a novel therapeutic target. This article comprehensively summarizes the molecular mechanism of m6A demethylase involved in the occurrence and development of gastric cancer, and the relationship between its expression and function, and biological characteristics of m6A demethylase were reviewed, aiming to provide new research ideas for early diagnosis and targeted treatment of gastric cancer.

Cite this article

Shuang JIANG , Jiwei YU . Progress of research on m6A demethylases in gastric cancer[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024 , 44(2) : 271 -277 . DOI: 10.3969/j.issn.1674-8115.2024.02.014

References

1 SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
2 TUCK M T. Partial purification of a 6-methyladenine mRNA methyltransferase which modifies internal adenine residues[J]. Biochem J, 1992, 288(Pt 1): 233-240.
3 WANG X, HE C. Dynamic RNA modifications in posttranscriptional regulation[J]. Mol Cell, 2014, 56(1): 5-12.
4 OERUM S, MEYNIER V, CATALA M, et al. A comprehensive review of m6A/m6Am RNA methyltransferase structures[J]. Nucleic Acids Res, 2021, 49(13): 7239-7255.
5 LEE Y, CHOE J, PARK O H, et al. Molecular mechanisms driving mRNA degradation by m6A modification[J]. Trends Genet, 2020, 36(3): 177-188.
6 FRYE M, HARADA B T, BEHM M, et al. RNA modifications modulate gene expression during development[J]. Science, 2018, 361(6409): 1346-1349.
7 CHEN X Y, ZHANG J, ZHU J S. The role of m6A RNA methylation in human cancer[J]. Mol Cancer, 2019, 18(1): 103.
8 YUE B, SONG C L, YANG L X, et al. METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer[J]. Mol Cancer, 2019, 18(1): 142.
9 WANG Q, CHEN C, DING Q Q, et al. METTL3-mediated m6A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance[J]. Gut, 2020, 69(7): 1193-1205.
10 ZHANG C, ZHANG M Q, GE S, et al. Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K-Akt signaling in gastric cancer[J]. Cancer Med, 2019, 8(10): 4766-4781.
11 LIU N, ZHANG C, ZHANG L. WTAP-involved the m6A modification of lncRNA FAM83H-AS1 accelerates the development of gastric cancer[J]. Mol Biotechnol, 2023.DOI:10.1007/s12033-023-00810-2.
12 LIU Y, DA M. Wilms tumor 1 associated protein promotes epithelial mesenchymal transition of gastric cancer cells by accelerating TGF-β and enhances chemoradiotherapy resistance[J]. J Cancer Res Clin Oncol, 2023, 149(7): 3977-3988.
13 BAI X W, WONG C C, PAN Y S, et al. Loss of YTHDF1 in gastric tumors restores sensitivity to antitumor immunity by recruiting mature dendritic cells[J]. J Immunother Cancer, 2022, 10(2): e003663.
14 LIU T, YANG S, CHENG Y P, et al. The N6-methyladenosine (m6A) methylation gene YTHDF1 reveals a potential diagnostic role for gastric cancer[J]. Cancer Manag Res, 2020, 12: 11953-11964.
15 CHEN W, HE Q J, LIU J J, et al. PLAGL2 promotes snail expression and gastric cancer progression via UCA1/miR-145-5p/YTHDF1 axis[J]. Carcinogenesis, 2023, 44(4): 328-340.
16 YANG H, HU Y R, WENG M Z, et al. Hypoxia inducible lncRNA-CBSLR modulates ferroptosis through m6A-YTHDF2-dependent modulation of CBS in gastric cancer[J]. J Adv Res, 2022, 37: 91-106.
17 SHEN X D, ZHAO K, XU L M, et al. YTHDF2 inhibits gastric cancer cell growth by regulating FOXC2 signaling pathway[J]. Front Genet, 2020, 11: 592042.
18 HUANG Y, YAN J L, LI Q, et al. Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5[J]. Nucleic Acids Res, 2015, 43(1): 373-384.
19 ZHOU J, WAN J, GAO X W, et al. Dynamic m6A mRNA methylation directs translational control of heat shock response[J]. Nature, 2015, 526(7574): 591-594.
20 WANG X, LU Z K, GOMEZ A, et al. N6-methyladenosine-dependent regulation of messenger RNA stability[J]. Nature, 2014, 505(7481): 117-120.
21 WANG X, ZHAO B S, ROUNDTREE I A, et al. N6-methyladenosine modulates messenger RNA translation efficiency[J]. Cell, 2015, 161(6): 1388-1399.
22 LIU N, DAI Q, ZHENG G, et al. N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions[J]. Nature, 2015, 518(7540): 560-564.
23 UEDA Y, OOSHIO I, FUSAMAE Y, et al. AlkB homolog 3-mediated tRNA demethylation promotes protein synthesis in cancer cells[J]. Sci Rep, 2017, 7: 42271.
24 JIA G F, FU Y, ZHAO X, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO[J]. Nat Chem Biol, 2011, 7(12): 885-887.
25 LI Y, WU K, QUAN W, et al. The dynamics of FTO binding and demethylation from the m6A motifs[J]. RNA Biol, 2019, 16(9): 1179-1189.
26 MAUER J, LUO X B, BLANJOIE A, et al. Reversible methylation of m6Am in the 5' cap controls mRNA stability[J]. Nature, 2017, 541(7637): 371-375.
27 WEI J B, LIU F G, LU Z K, et al. Differential m6A, m6Am, and m1A demethylation mediated by FTO in the cell nucleus and cytoplasm[J]. Mol Cell, 2018, 71(6): 973-985.e5.
28 DINA C, MEYRE D, GALLINA S, et al. Variation in FTO contributes to childhood obesity and severe adult obesity[J]. Nat Genet, 2007, 39(6): 724-726.
29 SCUTERI A, SANNA S, CHEN W M, et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits[J]. PLoS Genet, 2007, 3(7): e115.
30 LI Y, SU R, DENG X, et al. FTO in cancer: functions, molecular mechanisms, and therapeutic implications[J]. Trends Cancer, 2022, 8(7): 598-614.
31 ZHENG G Q, DAHL J A, NIU Y M, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility[J]. Mol Cell, 2013, 49(1): 18-29.
32 TANG B, YANG Y H, KANG M, et al. m6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling[J]. Mol Cancer, 2020, 19(1): 3.
33 QU J W, YAN H M, HOU Y F, et al. RNA demethylase ALKBH5 in cancer: from mechanisms to therapeutic potential[J]. J Hematol Oncol, 2022, 15(1): 8.
34 JIANG Y, WAN Y C, GONG M, et al. RNA demethylase ALKBH5 promotes ovarian carcinogenesis in a simulated tumour microenvironment through stimulating NF-κB pathway[J]. J Cell Mol Med, 2020, 24(11): 6137-6148.
35 HU Y Y, GONG C L, LI Z B, et al. Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m6A modification[J]. Mol Cancer, 2022, 21(1): 34.
36 CHEN Z J, QI M J, SHEN B, et al. Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs[J]. Nucleic Acids Res, 2019, 47(5): 2533-2545.
37 SHIMURA T, KANDIMALLA R, OKUGAWA Y, et al. Novel evidence for m6A methylation regulators as prognostic biomarkers and FTO as a potential therapeutic target in gastric cancer[J]. Br J Cancer, 2022, 126(2): 228-237.
38 ZHANG L, HOU Y H, ASHKTORAB H, et al. The impact of C-MYC gene expression on gastric cancer cell[J]. Mol Cell Biochem, 2010, 344(1-2): 125-135.
39 YANG Z, JIANG X D, ZHANG Z H, et al. HDAC3-dependent transcriptional repression of FOXA2 regulates FTO/m6A/MYC signaling to contribute to the development of gastric cancer[J]. Cancer Gene Ther, 2021, 28(1-2): 141-155.
40 SU R, DONG L, LI C Y, et al. R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling[J]. Cell, 2018, 172(1-2): 90-105.e23.
41 GUO C M, CHU H J, GONG Z H, et al. HOXB13 promotes gastric cancer cell migration and invasion via IGF-1R upregulation and subsequent activation of PI3K/AKT/mTOR signaling pathway[J]. Life Sci, 2021, 278: 119522.
42 GUAN K L, LIU X, LI J H, et al. Expression status and prognostic value of m6A-associated genes in gastric cancer[J]. J Cancer, 2020, 11(10): 3027-3040.
43 GE L C, ZHANG N, CHEN Z J, et al. Level of N6-methyladenosine in peripheral blood RNA: a novel predictive biomarker for gastric cancer[J]. Clin Chem, 2020, 66(2): 342-351.
44 FENG S T, QIU G Q, YANG L H, et al. Omeprazole improves chemosensitivity of gastric cancer cells by m6A demethylase FTO-mediated activation of mTORC1 and DDIT3 up-regulation[J]. Biosci Rep, 2021, 41(1): BSR20200842.
45 ZHANG Y, GAO L X, WANG W, et al. m6A demethylase fat mass and obesity-associated protein regulates cisplatin resistance of gastric cancer by modulating autophagy activation through ULK1[J]. Cancer Sci, 2022, 113(9): 3085-3096.
46 YU H, ZHAO K, ZENG H, et al. N6-methyladenosine (m6A) methyltransferase WTAP accelerates the Warburg effect of gastric cancer through regulating HK2 stability[J]. Biomed Pharmacother, 2021, 133: 111075.
47 ZHOU Y, WANG Q, DENG H F, et al. N6-methyladenosine demethylase FTO promotes growth and metastasis of gastric cancer via m6A modification of caveolin-1 and metabolic regulation of mitochondrial dynamics[J]. Cell Death Dis, 2022, 13(1): 72.
48 ZHANG J, GUO S, PIAO H Y, et al. ALKBH5 promotes invasion and metastasis of gastric cancer by decreasing methylation of the lncRNA NEAT1[J]. J Physiol Biochem, 2019, 75(3): 379-389.
49 ZHANG C Z, ZHI W I, LU H Q, et al. Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217- and ALKBH5-mediated modulation of RNA methylation in breast cancer cells[J]. Oncotarget, 2016, 7(40): 64527-64542.
50 KONISHI N, NAKAMURA M, ISHIDA E, et al. High expression of a new marker PCA-1 in human prostate carcinoma[J]. Clin Cancer Res, 2005, 11(14): 5090-5097.
51 YAMATO I, SHO M, SHIMADA K, et al. PCA-1/ALKBH3 contributes to pancreatic cancer by supporting apoptotic resistance and angiogenesis[J]. Cancer Res, 2012, 72(18): 4829-4839.
52 PIL?YS T, MARCINKOWSKI M, KUKWA W, et al. ALKBH overexpression in head and neck cancer: potential target for novel anticancer therapy[J]. Sci Rep, 2019, 9(1): 13249.
53 TASAKI M, SHIMADA K, KIMURA H, et al. ALKBH3, a human AlkB homologue, contributes to cell survival in human non-small-cell lung cancer[J]. Br J Cancer, 2011, 104(4): 700-706.
54 WOO H H, CHAMBERS S K. Human ALKBH3-induced m1A demethylation increases the CSF-1 mRNA stability in breast and ovarian cancer cells[J]. Biochim Biophys Acta Gene Regul Mech, 2019, 1862(1): 35-46.
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