Inhibition of MAT2A-Related Methionine Metabolism Enhances The Efficacy of Cisplatin on Cisplatin-Resistant Cells in Lung Cancer

Document Type : Original Article


1 Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China

2 Precision Diagnosis and Treatment Center of Jinhua City, Jinhua, Zhejiang Province, China

3 Department of General Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China

4 Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China

5 Department of Respiratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China


Objective: Tumor drug resistance is a vital obstacle to chemotherapy in lung cancer. Methionine adenosyltransferase 
2A has been considered as a potential target for lung cancer treatment because targeting it can disrupt the tumorigenicity of lung tumor-initiating cells. In this study, we primarily observed the role of methionine metabolism in cisplatin-resistant lung cancer cells and the functional mechanism of MAT2A related to cisplatin resistance. 
Materials and Methods: In this experimental study, we assessed the half maximal inhibitory concentration (IC50) 
of cisplatin in different cell lines and cell viability via Cell Counting Kit-8. Western blotting and quantitative real-time 
polymerase chain reaction (qRT-PCR) was used to determine the expression of relative proteins and genes. Crystal violet staining was used to investigate cell proliferation. Additionally, we explored the transcriptional changes in lung 
cancer cells via RNA-seq.
Results: We found H460/DDP and PC-9 cells were more resistant to cisplatin than H460, and MAT2A was overexpressed 
in cisplatin-resistant cells. Interestingly, methionine deficiency enhanced the inhibitory effect of cisplatin on cell activity and the pro-apoptotic effect. Targeting MAT2A not only restrained cell viability and proliferation, but also contributed to 
sensitivity of H460/DDP to cisplatin. Furthermore, 4283 up-regulated and 5841 down-regulated genes were detected in 
H460/DDP compared with H460, and 71 signal pathways were significantly enriched. After treating H460/DDP cells with 
PF9366, 326 genes were up-regulated, 1093 genes were down-regulated, and 13 signaling pathways were significantly 
enriched. In TNF signaling pathway, CAS7 and CAS8 were decreased in H460/DDP cells, which increased by PF9366 
treatment. Finally, the global histone methylation (H3K4me3, H3K9me2, H3K27me3, H3K36me3) was reduced under 
methionine deficiency conditions, while H3K9me2 and H3K36me3 were decreased specially via PF9366. 
Conclusion: Methionine deficiency or MAT2A inhibition may modulate genes expression associated with apoptosis, 
DNA repair and TNF signaling pathways by regulating histone methylation, thus promoting the sensitivity of lung cancer 
cells to cisplatin. 


  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394-424.
  2. Nagasaka M, Gadgeel SM. Role of chemotherapy and targeted therapy in early-stage non-small cell lung cancer. Expert Rev Anticancer Ther. 2018; 18(1): 63-70.
  3. Rossi A, Di Maio M. Platinum-based chemotherapy in advanced non-small-cell lung cancer: optimal number of treatment cycles. Expert Rev Anticancer Ther. 2016; 16(6): 653-660.
  4. Terlizzi M, Colarusso C, Pinto A, Sorrentino R. Drug resistance in non-small cell lung cancer (NSCLC): Impact of genetic and nongenetic alterations on therapeutic regimen and responsiveness. Pharmacol Ther. 2019; 202: 140-148.
  5. Sullivan LB, Gui DY, Vander Heiden MG. Altered metabolite levels in cancer: implications for tumour biology and cancer therapy. Nat Rev Cancer. 2016; 16(11): 680-693.
  6. Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016; 16(10): 619- 634.
  7. Locasale JW. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer. 2013; 13(8): 572-583.
  8. Sanderson SM, Gao X, Dai Z, Locasale JW. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat Rev Cancer. 2019; 19(11): 625-637.
  9. Mazor KM, Dong L, Mao Y, Swanda RV, Qian SB, Stipanuk MH. Effects of single amino acid deficiency on mRNA translation are markedly different for methionine versus leucine. Sci Rep. 2018; 8(1): 8076.
  10. Chen K, Liu H, Liu Z, Luo S, Patz EF Jr, Moorman PG, et al. Genetic variants in RUNX3, AMD1 and MSRA in the methionine metabolic pathway and survival in nonsmall cell lung cancer patients. Int J Cancer. 2019; 145(3): 621-631.
  11. Wang K, Liu H, Liu J, Wang X, Teng L, Zhang J, et al. IL1RN mediates the suppressive effect of methionine deprivation on glioma proliferation. Cancer Lett. 2019; 454: 146-157. 12. Cyr AR, Domann FE. The redox basis of epigenetic modifications:

from mechanisms to functional consequences. Antioxid Redox Signal. 2011; 15(2): 551-589.

  1. Mehler MF. Epigenetics and the nervous system. Ann Neurol. 2008; 64(6): 602-617.
  2. O’Shea JJ, Lahesmaa R, Vahedi G, Laurence A, Kanno Y. Genomic views of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol. 2011; 11(4): 239-250.
  3. Tripathi SK, Lahesmaa R. Transcriptional and epigenetic regulation of T-helper lineage specification. Immunol Rev. 2014; 261(1): 62-83.
  4. Tomasi ML, Ryoo M, Ramani K, Tomasi I, Giordano P, Mato JM, et al. Methionine adenosyltransferase α2 sumoylation positivelyregulate Bcl-2 expression in human colon and liver cancer cells. Oncotarget. 2015; 6(35): 37706-37723.
  5. Wang L, Shi S, Guo Z, Zhang X, Han S, Yang A, et al. Overexpression of YAP and TAZ is an independent predictor of prognosis in colorectal cancer and related to the proliferation and metastasis of colon cancer cells. PLoS One. 2013; 8(6): e65539.
  6. Wang X, Guo X, Yu W, Li C, Gui Y, Cai Z. Expression of methionine adenosyltransferase 2A in renal cell carcinomas and potential mechanism for kidney carcinogenesis. BMC Cancer. 2014; 14: 196.
  7. Zhang W, Sviripa V, Chen X, Shi J, Yu T, Hamza A, et al. Fluorinated N,N-dialkylaminostilbenes repress colon cancer by targeting methionine S-adenosyltransferase 2A. ACS Chem Biol. 2013; 8(4): 796-803.
  8. Wang Z, Yip LY, Lee JHJ, Wu Z, Chew HY, Chong PKW, et al. Methionine is a metabolic dependency of tumor-initiating cells. Nat Med. 2019; 25(5): 825-837.
  9. Zhao X, Fu J, Tang W, Yu L, Xu W. Inhibition of serine metabolism promotes resistance to cisplatin in gastric cancer. Onco Targets Ther. 2020; 13: 4833-4842.
  10. Trapnell C, Pachter L, Salzberg SL. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009; 25(9): 1105-1111.
  11. Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, et al. Transcript assembly and quantification by RNASeq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010; 28(5): 511-515.
  12. Wang L, Feng Z, Wang X, Wang X, Zhang X. DEGseq: an R package for identifying differentially expressed genes from RNA-seq data. Bioinformatics. 2010; 26(1): 136-138.
  13. Yousafzai NA, Zhou Q, Xu W, Shi Q, Xu J, Feng L, et al. SIRT1 deacetylated and stabilized XRCC1 to promote chemoresistance in lung cancer. Cell Death Dis. 2019; 10(5): 363.
  14. Poirson-Bichat F, Gonçalves RA, Miccoli L, Dutrillaux B, Poupon MF. Methionine depletion enhances the antitumoral efficacy of cytotoxic agents in drug-resistant human tumor xenografts. Clin Cancer Res. 2000; 6(2): 643-653.
  15. Chen H, Xia M, Lin M, Yang H, Kuhlenkamp J, Li T, et al. Role of methionine adenosyltransferase 2A and S-adenosylmethionine in mitogen-induced growth of human colon cancer cells. Gastroenterology. 2007; 133(1): 207-218.
  16. Quinlan CL, Kaiser SE, Bolaños B, Nowlin D, Grantner R, Karlicek- Bryant S, et al. Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A. Nat Chem Biol. 2017; 13(7): 785-792.
  17. Sinclair LV, Howden AJ, Brenes A, Spinelli L, Hukelmann JL, Macintyre AN, et al. Antigen receptor control of methionine metabolism in T cells. Elife. 2019; 8: e44210.
  18. Dai XJ, Tao JH, Fang X, Xia Y, Li XM, Wang YP, et al. Changes of Treg/Th17 ratio in spleen of acute gouty arthritis rat induced by MSU crystals. Inflammation. 2018; 41(5): 1955-1964.
  19. Roy DG, Chen J, Mamane V, Ma EH, Muhire BM, Sheldon RD, et al. Methionine metabolism shapes t helper cell responses through regulation of epigenetic reprogramming. Cell Metab. 2020; 31(2): 250-266.e9.
  20. Amable L. Cisplatin resistance and opportunities for precision medicine. Pharmacol Res. 2016; 106: 27-36.
  21. Bauerle MR, Schwalm EL, Booker SJ. Mechanistic diversity of radical S-adenosylmethionine (SAM)-dependent methylation. J Biol Chem. 2015; 290(7): 3995-4002.
  22. Gut P, Verdin E. The nexus of chromatin regulation and intermediary metabolism. Nature. 2013; 502(7472): 489-498.
  23. García-Trevijano ER, Latasa MU, Carretero MV, Berasain C, Mato JM, Avila MA. S-adenosylmethionine regulates MAT1A and MAT2A gene expression in cultured rat hepatocytes: a new role for S-adenosylmethionine in the maintenance of the differentiated status of the liver. FASEB J. 2000; 14(15): 2511-2518.
  24. Maldonado LY, Arsene D, Mato JM, Lu SC. Methionine adenosyltransferases in cancers: mechanisms of dysregulation and implications for therapy. Exp Biol Med (Maywood). 2018; 243(2): 107-117.
  25. Lu SC, Mato JM. S-Adenosylmethionine in cell growth, apoptosis and liver cancer. J Gastroenterol Hepatol. 2008; 23 Suppl 1: S73-S77.
  26. Balkwill F. TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev. 2006; 25(3): 409-416.
  27. Hyun K, Jeon J, Park K, Kim J. Writing, erasing and reading histone lysine methylations. Exp Mol Med. 2017; 49(4): e324.
  28. Shen E, Shulha H, Weng Z, Akbarian S. Regulation of histone H3K4 methylation in brain development and disease. Philos Trans R Soc Lond B Biol Sci. 2014; 369(1652): 20130514.