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MTHFD2 promotes esophageal squamous cell carcinoma progression via m6A modification‑mediated upregulation and modulation of the PEBP1‑RAF1 interaction

  • Authors:
    • Huijun Zhou
    • Han Gong
    • Xiaohui Zeng
    • Chong Zeng
    • Dian Liu
    • Jie Liu
    • Yingying Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology and Urology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan 410013, P.R. China, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan 410011, P.R. China, Department of Oncology, Hunan Institute of Schistosomiasis Control/The Third Hospital of Hunan Province, Yueyang, Hunan 414000, P.R. China, Department of Respiratory and Critical Care Medicine, The Seventh Affiliated Hospital, Hengyang Medical School, University of South China, Changsha, Hunan 410119, P.R. China, Department of Lymphoma and Abdominal Radiotherapy, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan 410013, P.R. China, Department of Pathology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan 410004, P.R. China, Department of Oncology, Xiangya Hospital of Central South University, Changsha, Hunan 410078, P.R. China
    Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 68
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    Published online on: February 28, 2025
       https://doi.org/10.3892/ijmm.2025.5509
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Abstract

One‑carbon metabolism plays an important role in cancer progression. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial enzyme in one‑carbon metabolism, is dysregulated in several cancer types. However, the precise role and mechanisms of MTHFD2 in esophageal squamous cell carcinoma (ESCC) remain unclear. The present study unravels the multifaceted mechanisms by which MTHFD2 contributes to ESCC pathogenesis. Bioinformatics analyses revealed significant upregulation of MTHFD2 in ESCC tumor tissues, which was associated with advanced disease stage and poor patient prognosis. Validating these findings in clinical samples, MTHFD2 overexpression was confirmed through immunohistochemistry, Reverse transcription‑quantitative PCR and western blotting. Knockdown of MTHFD2 inhibited ESCC cell viability, colony formation, invasion, and tumor growth in vivo, indicating its oncogenic potential. Mechanistically, the present study elucidated a novel regulatory axis involving N6‑methyladenosine modification and MTHFD2 mRNA stability. Specifically, methyltransferase‑like 3 (METTL3) and insulin‑like growth factor 2 mRNA binding protein 2 (IGF2BP2) were identified as key mediators of m6A‑dependent stabilization of MTHFD2 mRNA, contributing to its elevated expression in ESCC. Furthermore, MTHFD2 was found to activate PI3K/AKT and ERK signaling pathways by modulating interaction between phosphatidylethanolamine‑binding protein 1 (PEBP1) and raf‑1 proto‑oncogene (RAF1). This modulation was achieved through direct binding of MTHFD2 to PEBP1, disrupting the inhibitory effect of PEBP1 on RAF1 and promoting downstream pathway activation. The oncogenic functions of MTHFD2 were attenuated upon PEBP1 knockdown, underscoring the role of the MTHFD2‑PEBP1 axis in ESCC progression. In summary, the present study uncovers a novel regulatory mechanism involving m6A modification and the MTHFD2‑PEBP1 axis, unveiling potential therapeutic avenues for targeting MTHFD2 in ESCC.
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View References

1 

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI

2 

DaSilva LL, Aguiar PN Jr and de Lima Lopes G: Immunotherapy for advanced esophageal squamous cell carcinoma-renewed enthusiasm and a lingering challenge. JAMA Oncol. 7:1613–1614. 2021. View Article : Google Scholar : PubMed/NCBI

3 

Li Y, Yang B, Ma Y, Peng X, Wang Z, Sheng B, Wei Z, Cui Y and Liu Z: Phosphoproteomics reveals therapeutic targets of esophageal squamous cell carcinoma. Signal Transduct Target Ther. 6:3812021. View Article : Google Scholar : PubMed/NCBI

4 

Jiang K, Yin X, Zhang Q, Yin J, Tang Q, Xu M, Wu L, Shen Y, Zhou Z, Yu H and Yan S: STC2 activates PRMT5 to induce radioresistance through DNA damage repair and ferroptosis pathways in esophageal squamous cell carcinoma. Redox Biol. 60:1026262023. View Article : Google Scholar : PubMed/NCBI

5 

Pavlova NN, Zhu J and Thompson CB: The hallmarks of cancer metabolism: Still emerging. Cell Metab. 34:355–577. 2022. View Article : Google Scholar : PubMed/NCBI

6 

Locasale JW: Serine, glycine and one-carbon units: Cancer metabolism in full circle. Nat Rev Cancer. 13:572–583. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Pan S, Fan M, Liu Z, Li X and Wang H: Serine, glycine and one-carbon metabolism in cancer (Review). Int J Oncol. 58:158–170. 2021. View Article : Google Scholar : PubMed/NCBI

8 

Ducker GS and Rabinowitz JD: One-carbon metabolism in health and disease. Cell Metab. 25:27–42. 2017. View Article : Google Scholar :

9 

Nilsson R, Jain M, Madhusudhan N, Sheppard NG, Strittmatter L, Kampf C, Huang J, Asplund A and Mootha VK: Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun. 5:31282014. View Article : Google Scholar : PubMed/NCBI

10 

Zhu Z and Leung GKK: More than a metabolic enzyme: MTHFD2 as a novel target for anticancer therapy? Front Oncol. 10:6582020. View Article : Google Scholar : PubMed/NCBI

11 

Cui X, Su H, Yang J, Wu X, Huo K, Jing X and Zhang S: Up-regulation of MTHFD2 is associated with clinicopathological characteristics and poor survival in ovarian cancer, possibly by regulating MOB1A signaling. J Ovarian Res. 15:232022. View Article : Google Scholar : PubMed/NCBI

12 

Shi LF, Zhang Q, Shou XY and Niu HJ: Expression and prognostic value identification of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in brain low-grade glioma. Int J Gen Med. 14:4517–4527. 2021. View Article : Google Scholar : PubMed/NCBI

13 

Geng QQ, Wu QF, Zhang Y, Zhang GJ, Fu JK and Chen NZ: Clinical significance of circ-MTHFD2 in diagnosis, pathological staging and prognosis of NSCLC. Eur Rev Med Pharmacol Sci. 24:9473–9479. PubMed/NCBI

14 

Ju HQ, Lu YX, Chen DL, Zuo ZX, Liu ZX, Wu QN, Mo HY, Wang ZX, Wang DS, Pu HY, et al: Modulation of redox homeostasis by inhibition of MTHFD2 in colorectal cancer: Mechanisms and therapeutic implications. J Natl Cancer Inst. 111:584–596. 2019. View Article : Google Scholar :

15 

An Y and Duan H: The role of m6A RNA methylation in cancer metabolism. Mol Cancer. 21:142022. View Article : Google Scholar : PubMed/NCBI

16 

Liu T, Wei Q, Jin J, Luo Q, Liu Y, Yang Y, Cheng C, Li L, Pi J, Si Y, et al: The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic Acids Res. 48:3816–3831. 2020. View Article : Google Scholar : PubMed/NCBI

17 

Zeng C, Huang W, Li Y and Weng H: Roles of METTL3 in cancer: Mechanisms and therapeutic targeting. J Hematol Oncol. 13:1172020. View Article : Google Scholar : PubMed/NCBI

18 

Cui Y, Zhang C, Ma S, Li Z, Wang W, Li Y, Ma Y, Fang J, Wang Y, Cao W and Guan F: RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma. J Exp Clin Cancer Res. 40:2942021. View Article : Google Scholar : PubMed/NCBI

19 

Wang W, Shao F, Yang X, Wang J, Zhu R, Yang Y, Zhao G, Guo D, Sun Y, Wang J, et al: METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N(6)-methyladenosine-dependent YTHDF binding. Nat Commun. 12:38032021. View Article : Google Scholar : PubMed/NCBI

20 

Zhao Y, Li Y, Zhu R, Feng R, Cui H, Yu X, Huang F, Zhang R, Chen X, Li L, et al: RPS15 interacted with IGF2BP1 to promote esophageal squamous cell carcinoma development via recognizing m6A modification. Signal Transduct Target Ther. 8:2242023. View Article : Google Scholar

21 

Li Y, Niu C, Wang N, Huang X, Cao S, Cui S, Chen T, Huo X and Zhou R: The role of m6A modification and m6A regulators in esophageal cancer. Cancers (Basel). 14:51392022. View Article : Google Scholar

22 

Qi ZH, Xu HX, Zhang SR, Xu JZ, Li S, Gao HL, Jin W, Wang WQ, Wu CT, Ni QX, et al: RIPK4/PEBP1 axis promotes pancreatic cancer cell migration and invasion by activating RAF1/MEK/ERK signaling. Int J Oncol. 52:1105–1116. 2018.PubMed/NCBI

23 

Yang X, Wang Y, Lu P, Shen Y, Zhao X, Zhu Y, Jiang Z, Yang H, Pan H, Zhao L, et al: PEBP1 suppresses HIV transcription and induces latency by inactivating MAPK/NF-kappaB signaling. EMBO Rep. 21:e493052020. View Article : Google Scholar

24 

Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, Sabedot TS, Malta TM, Pagnotta SM, Castiglioni I, et al: TCGAbiolinks: An R/bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 44:e712016. View Article : Google Scholar :

25 

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, Li B and Liu XS: TIMER: A web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 77:e108–e110. 2017. View Article : Google Scholar : PubMed/NCBI

26 

Nagy A, Munkacsy G and Gyorffy B: Pancancer survival analysis of cancer hallmark genes. Sci Rep. 11:60472021. View Article : Google Scholar : PubMed/NCBI

27 

Zhou H, Zeng C, Liu J, Luo H and Huang W: F-box protein 43, stabilized by N6-methyladenosine methylation, enhances hepatocellular carcinoma cell growth and invasion via promoting p53 degradation in a ubiquitin conjugating enzyme E2 c-dependent manner. Cancers (Basel). 15:9572023. View Article : Google Scholar : PubMed/NCBI

28 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar

29 

Yang Q, Zhu W and Gong H: Subtype classification based on T cell proliferation-related regulator genes and risk model for predicting outcomes of lung adenocarcinoma. Front Immunol. 14:11484832023. View Article : Google Scholar : PubMed/NCBI

30 

Zhang P, Li H, Gong H, Tian Y, Chen F, Li X, Xie C, Tu C, Qian S, Tan Y, et al: c-Myc-XRCC2-FOS axis promotes the proliferation and the resistance to doxorubicin of NSCLC. Biomed Pharmacother. 179:1173152024. View Article : Google Scholar : PubMed/NCBI

31 

Song L, Gong H, Lin C, Wang C, Liu L, Wu J, Li M and Li J: Flotillin-1 promotes tumor necrosis factor-alpha receptor signaling and activation of NF-kappaB in esophageal squamous cell carcinoma cells. Gastroenterology. 143:995–1005.e12. 2012. View Article : Google Scholar

32 

Carbone L, Carbone ET, Yi EM, Bauer DB, Lindstrom KA, Parker JM, Austin JA, Seo Y, Gandhi AD and Wilkerson JD: Assessing cervical dislocation as a humane euthanasia method in mice. J Am Assoc Lab Anim Sci. 51:352–356. 2012.PubMed/NCBI

33 

Sendinc E and Shi Y: RNA m6A methylation across the transcriptome. Mol Cell. 83:428–441. 2023. View Article : Google Scholar : PubMed/NCBI

34 

Zhou Y, Zeng P, Li YH, Zhang Z and Cui Q: SRAMP: Prediction of mammalian N6-methyladenosine (m6A) sites based on sequence-derived features. Nucleic Acids Res. 44:e912016. View Article : Google Scholar : PubMed/NCBI

35 

Oughtred R, Stark C, Breitkreutz BJ, Rust J, Boucher L, Chang C, Kolas N, O'Donnell L, Leung G, McAdam R, et al: The BioGRID interaction database: 2019 update. Nucleic Acids Res. 47:D529–D41. 2019. View Article : Google Scholar :

36 

Abd Alla J and Quitterer U: The RAF kinase inhibitor protein (RKIP): Good as tumour suppressor, bad for the heart. Cells. 11:6542022. View Article : Google Scholar : PubMed/NCBI

37 

He H, Li PC, Jia W, Hu B and Ji CS: High expression of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in esophageal squamous cell carcinoma and its clinical prognostic significance. Med Sci Monit. 26:e9202592020. View Article : Google Scholar : PubMed/NCBI

38 

Soares-Lima SC, Gonzaga IM, Camuzi D, Nicolau-Neto P, Vieira da Silva R, Guaraldi S, Ferreira MA, Hernandez-Vargas H, Herceg Z and Ribeiro Pinto LF: IL6 and BCL3 expression are potential biomarkers in esophageal squamous cell carcinoma. Front Oncol. 11:7224172021. View Article : Google Scholar : PubMed/NCBI

39 

Yang Y, Huang X, Zhou L, Deng T, Ning T, Liu R, Zhang L, Bai M, Zhang H, Li H and Ba Y: Clinical use of tumor biomarkers in prediction for prognosis and chemotherapeutic effect in esophageal squamous cell carcinoma. BMC Cancer. 19:5262019. View Article : Google Scholar : PubMed/NCBI

40 

Lu F, Chen W, Jiang T, Cheng C, Wang B, Lu Z, Huang G, Qiu J, Wei W, Yang M and Huang X: Expression profile, clinical significance and biological functions of IGF2BP2 in esophageal squamous cell carcinoma. Exp Ther Med. 23:2522022. View Article : Google Scholar : PubMed/NCBI

41 

Shi Y, Xu Y, Yao J, Yan C, Su H, Zhang X, Chen E and Ying K: MTHFD2 promotes tumorigenesis and metastasis in lung adenocarcinoma by regulating AKT/GSK-3beta/beta-catenin signalling. J Cell Mol Med. 25:7013–7027. 2021. View Article : Google Scholar : PubMed/NCBI

42 

Deng X, Liu X, Hu B, Liu J, Fu B and Zhang W: Upregulation of MTHFD2 is associated with PD-L1 activation in bladder cancer via the PI3K/AKT pathway. Int J Mol Med. 51:142023. View Article : Google Scholar :

43 

Wu S, Cai W, Shi Z, Ming X, Yang X, Zhou Y, Chen X and Yang M: Knockdown of MTHFD2 inhibits proliferation and migration of nasopharyngeal carcinoma cells through the ERK signaling pathway. Biochem Biophys Res Commun. 614:47–55. 2022. View Article : Google Scholar : PubMed/NCBI

44 

Mo X, Liu Q, Liang K and Song Y: Interference with MTHFD2 induces ferroptosis in ovarian cancer cells through ERK signaling to suppress tumor malignant progression. J Bioenerg Biomembr. 56:333–345. 2024. View Article : Google Scholar : PubMed/NCBI

45 

Zhang H, Zhu S, Zhou H, Li R, Xia X and Xiong H: Identification of MTHFD2 as a prognostic biomarker and ferroptosis regulator in triple-negative breast cancer. Front Oncol. 13:10983572023. View Article : Google Scholar : PubMed/NCBI

46 

Mo HY, Wang RB, Ma MY, Zhang Y, Li XY, Wen WR, Han Y and Tian T: MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions. Redox Rep. 29:23454552024. View Article : Google Scholar : PubMed/NCBI

47 

Wang J, Yu Z, Jiang Y, Le T, Wu Y, Li Z, Zhang G, Wu F and Ma H: Downregulation of MTHFD2 inhibits proliferation and enhances chemosensitivity in hepatocellular carcinoma via PI3K/AKT pathway. Front Biosci (Landmark Ed). 29:352024. View Article : Google Scholar : PubMed/NCBI

48 

Zhu Z, Kiang KM, Li N, Liu J, Zhang P, Jin L, He X, Zhang S and Leung GK: Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma. Cancer Lett. 549:2159032022. View Article : Google Scholar : PubMed/NCBI

49 

Zhou F, Yuan Z, Gong Y, Li L, Wang Y, Wang X, Ma C, Yang L, Liu Z, Wang L, et al: Pharmacological targeting of MTHFD2 suppresses NSCLC via the regulation of ILK signaling pathway. Biomed Pharmacother. 161:1144122023. View Article : Google Scholar : PubMed/NCBI

50 

Ramos L, Henriksson M, Helleday T and Green AC: Targeting MTHFD2 to exploit cancer-specific metabolism and the DNA damage response. Cancer Res. 84:9–16. 2024. View Article : Google Scholar

51 

Vesely MD, Zhang T and Chen L: Resistance mechanisms to anti-PD cancer immunotherapy. Annu Rev Immunol. 40:45–74. 2022. View Article : Google Scholar : PubMed/NCBI

52 

Shang M, Yang H, Yang R, Chen T, Fu Y, Li Y, Fang X, Zhang K, Zhang J, Li H, et al: The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation. Nat Commun. 12:19402021. View Article : Google Scholar : PubMed/NCBI

53 

Li L, Zhang Y, Hu W, Zou F, Ning J, Rao T, Ruan Y, Yu W and Cheng F: MTHFD2 promotes PD-L1 expression via activation of the JAK/STAT signalling pathway in bladder cancer. J Cell Mol Med. 27:2922–2936. 2023. View Article : Google Scholar : PubMed/NCBI

54 

Shang M, Ni L, Shan X, Cui Y, Hu P, Ji Z, Shen L, Zhang Y, Zhou J, Chen B, et al: MTHFD2 reprograms macrophage polarization by inhibiting PTEN. Cell Rep. 42:1124812023. View Article : Google Scholar : PubMed/NCBI

55 

Sugiura A, Andrejeva G, Voss K, Heintzman DR, Xu X, Madden MZ, Ye X, Beier KL, Chowdhury NU, Wolf MM, et al: MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function. Immunity. 55:65–81.e9. 2022. View Article : Google Scholar :

56 

Hashimoto K, Nishimura S, Ito T, Kakinoki R and Akagi M: Immunohistochemical expression and clinicopathological assessment of PD-1, PD-L1, NY-ESO-1, and MAGE-A4 expression in highly aggressive soft tissue sarcomas. Eur J Histochem. 66:33932022. View Article : Google Scholar : PubMed/NCBI

57 

Chu X, Tian W, Wang Z, Zhang J and Zhou R: Co-inhibition of TIGIT and PD-1/PD-L1 in cancer immunotherapy: Mechanisms and clinical trials. Mol Cancer. 22:1012023. View Article : Google Scholar

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Spandidos Publications style
Zhou H, Gong H, Zeng X, Zeng C, Liu D, Liu J and Zhang Y: MTHFD2 promotes esophageal squamous cell carcinoma progression via m6A modification‑mediated upregulation and modulation of the PEBP1‑RAF1 interaction. Int J Mol Med 55: 68, 2025.
APA
Zhou, H., Gong, H., Zeng, X., Zeng, C., Liu, D., Liu, J., & Zhang, Y. (2025). MTHFD2 promotes esophageal squamous cell carcinoma progression via m6A modification‑mediated upregulation and modulation of the PEBP1‑RAF1 interaction. International Journal of Molecular Medicine, 55, 68. https://doi.org/10.3892/ijmm.2025.5509
MLA
Zhou, H., Gong, H., Zeng, X., Zeng, C., Liu, D., Liu, J., Zhang, Y."MTHFD2 promotes esophageal squamous cell carcinoma progression via m6A modification‑mediated upregulation and modulation of the PEBP1‑RAF1 interaction". International Journal of Molecular Medicine 55.5 (2025): 68.
Chicago
Zhou, H., Gong, H., Zeng, X., Zeng, C., Liu, D., Liu, J., Zhang, Y."MTHFD2 promotes esophageal squamous cell carcinoma progression via m6A modification‑mediated upregulation and modulation of the PEBP1‑RAF1 interaction". International Journal of Molecular Medicine 55, no. 5 (2025): 68. https://doi.org/10.3892/ijmm.2025.5509
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Spandidos Publications style
Zhou H, Gong H, Zeng X, Zeng C, Liu D, Liu J and Zhang Y: MTHFD2 promotes esophageal squamous cell carcinoma progression via m6A modification‑mediated upregulation and modulation of the PEBP1‑RAF1 interaction. Int J Mol Med 55: 68, 2025.
APA
Zhou, H., Gong, H., Zeng, X., Zeng, C., Liu, D., Liu, J., & Zhang, Y. (2025). MTHFD2 promotes esophageal squamous cell carcinoma progression via m6A modification‑mediated upregulation and modulation of the PEBP1‑RAF1 interaction. International Journal of Molecular Medicine, 55, 68. https://doi.org/10.3892/ijmm.2025.5509
MLA
Zhou, H., Gong, H., Zeng, X., Zeng, C., Liu, D., Liu, J., Zhang, Y."MTHFD2 promotes esophageal squamous cell carcinoma progression via m6A modification‑mediated upregulation and modulation of the PEBP1‑RAF1 interaction". International Journal of Molecular Medicine 55.5 (2025): 68.
Chicago
Zhou, H., Gong, H., Zeng, X., Zeng, C., Liu, D., Liu, J., Zhang, Y."MTHFD2 promotes esophageal squamous cell carcinoma progression via m6A modification‑mediated upregulation and modulation of the PEBP1‑RAF1 interaction". International Journal of Molecular Medicine 55, no. 5 (2025): 68. https://doi.org/10.3892/ijmm.2025.5509
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