METTL3 Expression is Associated with Glycolysis Metabolism and Sensitivity to Glycolytic Stress in Hepatocellular Carcinoma

Overview

Journal Cancer Med

Specialty Oncology

Date 2020 Feb 19

PMID 32068977

Citations 48

Authors

Ye Lin

Xiangling Wei

Zhixiang Jian

Xuewen Zhang

Affiliations

Soon will be listed here.

Abstract

METTL3 is an RNA methyltransferase implicated in the control of cell differentiation and proliferation in embryonic development and cancer. The current study was aimed to explore the function and underlying mechanism of METTL3 in hepatocellular carcinoma (HCC). We evaluated the expression and prognostic significance of METTL3 in 100 HCC cases and TCGA dataset. In HCC cases, both the RNA and protein expression of METTL3 were significantly upregulated and associated with poor prognosis. Gene set enrichment analysis of transcriptional profiles in HCC specimens revealed that METTL3 expression was associated with impaired glucose metabolism and mTOR signal pathway. In Huh-7 and SMMC-7721 HCC cells, downregulation of METTL3 by siRNA interference inhibited glycolytic capacity, which was proved by the decreased intracellular glucose uptake and lactate production. In terms of mechanism, we found mTORC1 activity was impaired by downregulation of METTL3, additional silencing of METTL3 cannot further decrease the phosphorylation level of mTORC1 and glycolysis activity in Rapamycin-treated HCC cells. At last, we observed that downregulation of METTL3 synergizes with the glycolysis inhibitor 2-deoxyglucose (2-DG) to inhibit tumor growth in vitro. Our study provided evidence that METTL3 is involved in the regulation of glycolysis activity in HCC, suggesting that suppression of glycolysis via METTL3 inhibition was a potential treating strategy against HCC.

Citing Articles

SLC50A1 inhibits the doxorubicin sensitivity in hepatocellular carcinoma cells through regulating the tumor glycolysis.

Wang G, Jin W, Zhang L, Dong M, Zhang X, Zhou Z Cell Death Discov. 2024; 10(1):495.

PMID: 39695152 PMC: 11655560. DOI: 10.1038/s41420-024-02261-3.

Plasma-activated medium exerts tumor-specific inhibitory effect on hepatocellular carcinoma via disruption of the salvage pathway.

Bai Y, Dai C, Chen N, Zhou X, Li H, Xu Q J Clin Biochem Nutr. 2024; 75(2):91-101.

PMID: 39345287 PMC: 11425076. DOI: 10.3164/jcbn.23-112.

METTL3-mediated m6A modification of ZNF384 promotes hepatocellular carcinoma progression by transcriptionally activating ACSM1.

Zhang L, Wang J, Gui F, Peng F, Deng W, Zhu Q Clin Transl Oncol. 2024; .

PMID: 39342516 DOI: 10.1007/s12094-024-03701-3.

Progression of mA in the tumor microenvironment: hypoxia, immune and metabolic reprogramming.

Han X, Zhu Y, Ke J, Zhai Y, Huang M, Zhang X Cell Death Discov. 2024; 10(1):331.

PMID: 39033180 PMC: 11271487. DOI: 10.1038/s41420-024-02092-2.

The Role of N6-methyladenosine Modification in Gametogenesis and Embryogenesis: Impact on Fertility.

Wang Y, Yang C, Sun H, Jiang H, Zhang P, Huang Y Genomics Proteomics Bioinformatics. 2024; 22(4).

PMID: 38937660 PMC: 11514847. DOI: 10.1093/gpbjnl/qzae050.

References

Liu J, Eckert M, Harada B, Liu S, Lu Z, Yu K . mA mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer. Nat Cell Biol. 2018; 20(9):1074-1083. PMC: 6245953. DOI: 10.1038/s41556-018-0174-4. View

Liberti M, Locasale J . The Warburg Effect: How Does it Benefit Cancer Cells?. Trends Biochem Sci. 2016; 41(3):211-218. PMC: 4783224. DOI: 10.1016/j.tibs.2015.12.001. View

Hua W, Zhao Y, Jin X, Yu D, He J, Xie D . METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition. Gynecol Oncol. 2018; 151(2):356-365. DOI: 10.1016/j.ygyno.2018.09.015. View

Kurtoglu M, Maher J, Lampidis T . Differential toxic mechanisms of 2-deoxy-D-glucose versus 2-fluorodeoxy-D-glucose in hypoxic and normoxic tumor cells. Antioxid Redox Signal. 2007; 9(9):1383-90. DOI: 10.1089/ars.2007.1714. View

Chen M, Wei L, Law C, Tsang F, Shen J, Cheng C . RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology. 2017; 67(6):2254-2270. DOI: 10.1002/hep.29683. View

Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L . A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2013; 10(2):93-5. PMC: 3911877. DOI: 10.1038/nchembio.1432. View

Pusapati R, Daemen A, Wilson C, Sandoval W, Gao M, Haley B . mTORC1-Dependent Metabolic Reprogramming Underlies Escape from Glycolysis Addiction in Cancer Cells. Cancer Cell. 2016; 29(4):548-562. DOI: 10.1016/j.ccell.2016.02.018. View

Li X, Tang J, Huang W, Wang F, Li P, Qin C . The M6A methyltransferase METTL3: acting as a tumor suppressor in renal cell carcinoma. Oncotarget. 2017; 8(56):96103-96116. PMC: 5707084. DOI: 10.18632/oncotarget.21726. View

Taketo K, Konno M, Asai A, Koseki J, Toratani M, Satoh T . The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells. Int J Oncol. 2018; 52(2):621-629. DOI: 10.3892/ijo.2017.4219. View

10.

Choe J, Lin S, Zhang W, Liu Q, Wang L, Ramirez-Moya J . mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature. 2018; 561(7724):556-560. PMC: 6234840. DOI: 10.1038/s41586-018-0538-8. View

11.

Pavlova N, Thompson C . The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016; 23(1):27-47. PMC: 4715268. DOI: 10.1016/j.cmet.2015.12.006. View

12.

DeWaal D, Nogueira V, Terry A, Patra K, Jeon S, Guzman G . Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun. 2018; 9(1):446. PMC: 5792493. DOI: 10.1038/s41467-017-02733-4. View

13.

Tong J, Flavell R, Li H . RNA mA modification and its function in diseases. Front Med. 2018; 12(4):481-489. DOI: 10.1007/s11684-018-0654-8. View

14.

Lin Y, Wei X, Jian Z, Zhang X . METTL3 expression is associated with glycolysis metabolism and sensitivity to glycolytic stress in hepatocellular carcinoma. Cancer Med. 2020; 9(8):2859-2867. PMC: 7163109. DOI: 10.1002/cam4.2918. View

15.

Xu K, Yang Y, Feng G, Sun B, Chen J, Li Y . Mettl3-mediated mA regulates spermatogonial differentiation and meiosis initiation. Cell Res. 2017; 27(9):1100-1114. PMC: 5587845. DOI: 10.1038/cr.2017.100. View

16.

Shi H, Zhang X, Weng Y, Lu Z, Liu Y, Lu Z . mA facilitates hippocampus-dependent learning and memory through YTHDF1. Nature. 2018; 563(7730):249-253. PMC: 6226095. DOI: 10.1038/s41586-018-0666-1. View

17.

Watson I, Takahashi K, Futreal P, Chin L . Emerging patterns of somatic mutations in cancer. Nat Rev Genet. 2013; 14(10):703-18. PMC: 4014352. DOI: 10.1038/nrg3539. View

18.

Wu Y, Xie L, Wang M, Xiong Q, Guo Y, Liang Y . Mettl3-mediated mA RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis. Nat Commun. 2018; 9(1):4772. PMC: 6235890. DOI: 10.1038/s41467-018-06898-4. View

19.

Arai T, Kano F, Murata M . Translocation of forkhead box O1 to the nuclear periphery induces histone modifications that regulate transcriptional repression of PCK1 in HepG2 cells. Genes Cells. 2015; 20(4):340-57. DOI: 10.1111/gtc.12226. View

20.

Dutchak P, Estill-Terpack S, Plec A, Zhao X, Yang C, Chen J . Loss of a Negative Regulator of mTORC1 Induces Aerobic Glycolysis and Altered Fiber Composition in Skeletal Muscle. Cell Rep. 2018; 23(7):1907-1914. PMC: 6038807. DOI: 10.1016/j.celrep.2018.04.058. View