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Hypoxia-induced SHMT2 protein lactylation facilitates glycolysis and stemness of esophageal cancer cells

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Abstract

Esophageal cancer (EC) is a familiar digestive tract tumor with highly lethal. The hypoxic environment has been demonstrated to be a significant factor in modulating malignant tumor progression and is strongly associated with the abnormal energy metabolism of tumor cells. Serine hydroxymethyl transferase 2 (SHMT2) is one of the most frequently expressed metabolic enzymes in human malignancies. The study was designed to investigate the biological functions and regulation mechanisms of SHMT2 in EC under hypoxia. We conducted RT-qPCR to assess SHMT2 levels in EC tissues and cells (TE-1 and EC109). EC cells were incubated under normoxia and hypoxia, respectively, and altered SHMT2 expression was evaluated through RT-qPCR, western blot, and immunofluorescence. The biological functions of SHMT2 on EC cells were monitored by performing CCK-8, EdU, transwell, sphere formation, glucose uptake, and lactate production assays. The SHMT2 protein lactylation was measured by immunoprecipitation and western blot. In addition, SHMT2-interacting proteins were analyzed by bioinformatics and validated by rescue experiments. SHMT2 was notably upregulated in EC tissues and cells. Hypoxia elevated SHMT2 protein expression, augmenting EC cell proliferation, migration, invasion, stemness, and glycolysis. In addition, hypoxia triggered lactylation of the SHMT2 protein and enhanced its stability. SHMT2 knockdown impeded the malignant phenotype of EC cells. Further mechanistic studies disclosed that SHMT2 is involved in EC progression by interacting with MTHFD1L. Hypoxia-induced SHMT2 protein lactylation and upregulated its protein level, which in turn enhanced MTHFD1L expression and accelerated the malignant progression of EC cells.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

References

  1. Cai Y, Lin J, Wei W, Chen P, Yao K (2022) Burden of esophageal cancer and its attributable risk factors in 204 countries and territories from 1990 to 2019. Front Public Health 10:952087. https://doi.org/10.3389/fpubh.2022.952087

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249. https://doi.org/10.3322/caac.21660

    Article  CAS  PubMed  Google Scholar 

  3. Liu CQ, Ma YL, Qin Q, Wang PH, Luo Y, Xu PF, Cui Y (2023) Epidemiology of esophageal cancer in 2020 and projections to 2030 and 2040. Thorac Cancer 14:3–11. https://doi.org/10.1111/1759-7714.14745

    Article  PubMed  Google Scholar 

  4. Sheikh M, Roshandel G, McCormack V, Malekzadeh R (2023) Current status and future prospects for esophageal cancer. Cancers (Basel). https://doi.org/10.3390/cancers15030765

    Article  PubMed  Google Scholar 

  5. Li Y, Zhao L, Li XF (2021) Hypoxia and the tumor microenvironment. Technol Cancer Res Treat 20:15330338211036304. https://doi.org/10.1177/15330338211036304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Vaupel P, Kelleher DK, Hockel M (2001) Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy. Semin Oncol 28:29–35. https://doi.org/10.1016/s0093-7754(01)90210-6

    Article  CAS  PubMed  Google Scholar 

  7. Bosco MC, D’Orazi G, Del Bufalo D (2020) Targeting hypoxia in tumor: a new promising therapeutic strategy. J Exp Clin Cancer Res 39:8. https://doi.org/10.1186/s13046-019-1517-0

    Article  PubMed  PubMed Central  Google Scholar 

  8. Qian J, Rankin EB (2019) Hypoxia-induced phenotypes that mediate tumor heterogeneity. Adv Exp Med Biol 1136:43–55. https://doi.org/10.1007/978-3-030-12734-3_3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Huang M, Yang L, Peng X, Wei S, Fan Q, Yang S, Li X, Li B, Jin H, Wu B, Liu J, Li H (2020) Autonomous glucose metabolic reprogramming of tumour cells under hypoxia: opportunities for targeted therapy. J Exp Clin Cancer Res 39:185. https://doi.org/10.1186/s13046-020-01698-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Warburg O (1956) On the origin of cancer cells. Science 123:309–314. https://doi.org/10.1126/science.123.3191.309

    Article  CAS  PubMed  Google Scholar 

  11. Hirschhaeuser F, Sattler UG, Mueller-Klieser W (2011) Lactate: a metabolic key player in cancer. Cancer Res 71:6921–6925. https://doi.org/10.1158/0008-5472.CAN-11-1457

    Article  CAS  PubMed  Google Scholar 

  12. Zhang Y, Zhai Z, Duan J, Wang X, Zhong J, Wu L, Li A, Cao M, Wu Y, Shi H, Zhong J, Guo Z (2022) Lactate: the mediator of metabolism and immunosuppression. Front Endocrinol (Lausanne) 13:901495. https://doi.org/10.3389/fendo.2022.901495

    Article  PubMed  Google Scholar 

  13. Doherty JR, Cleveland JL (2013) Targeting lactate metabolism for cancer therapeutics. J Clin Invest 123:3685–3692. https://doi.org/10.1172/JCI69741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, Liu W, Kim S, Lee S, Perez-Neut M, Ding J, Czyz D, Hu R, Ye Z, He M, Zheng YG, Shuman HA, Dai L, Ren B, Roeder RG, Becker L, Zhao Y (2019) Metabolic regulation of gene expression by histone lactylation. Nature 574:575–580. https://doi.org/10.1038/s41586-019-1678-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gu J, Zhou J, Chen Q, Xu X, Gao J, Li X, Shao Q, Zhou B, Zhou H, Wei S, Wang Q, Liang Y, Lu L (2022) Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-beta signaling in regulatory T cells. Cell Rep 40:111122. https://doi.org/10.1016/j.celrep.2022.111122

    Article  CAS  PubMed  Google Scholar 

  16. Xiong J, He J, Zhu J, Pan J, Liao W, Ye H, Wang H, Song Y, Du Y, Cui B, Xue M, Zheng W, Kong X, Jiang K, Ding K, Lai L, Wang Q (2022) Lactylation-driven METTL3-mediated RNA m(6)A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Mol Cell 82(1660–1677):e1610. https://doi.org/10.1016/j.molcel.2022.02.033

    Article  CAS  Google Scholar 

  17. Zeng Y, Zhang J, Xu M, Chen F, Zi R, Yue J, Zhang Y, Chen N, Chin YE (2021) Roles of mitochondrial serine hydroxymethyltransferase 2 (SHMT2) in human carcinogenesis. J Cancer 12:5888–5894. https://doi.org/10.7150/jca.60170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xie M, Pei DS (2021) Serine hydroxymethyltransferase 2: a novel target for human cancer therapy. Invest New Drugs 39:1671–1681. https://doi.org/10.1007/s10637-021-01144-z

    Article  CAS  PubMed  Google Scholar 

  19. Chen J, Na R, Xiao C, Wang X, Wang Y, Yan D, Song G, Liu X, Chen J, Lu H, Chen C, Tang H, Zhuang G, Fan G, Peng Z (2021) The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy. Oncogene 40:3974–3988. https://doi.org/10.1038/s41388-021-01815-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang X, Wang Z, Li X, Liu B, Liu M, Liu L, Chen S, Ren M, Wang Y, Yu M, Wang B, Zou J, Zhu WG, Yin Y, Gu W, Luo J (2018) SHMT2 desuccinylation by SIRT5 drives cancer cell proliferation. Cancer Res 78:372–386. https://doi.org/10.1158/0008-5472.CAN-17-1912

    Article  CAS  PubMed  Google Scholar 

  21. Kim D, Fiske BP, Birsoy K, Freinkman E, Kami K, Possemato RL, Chudnovsky Y, Pacold ME, Chen WW, Cantor JR, Shelton LM, Gui DY, Kwon M, Ramkissoon SH, Ligon KL, Kang SW, Snuderl M, Vander Heiden MG, Sabatini DM (2015) SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance. Nature 520:363–367. https://doi.org/10.1038/nature14363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Qin YR, Tang H, Xie F, Liu H, Zhu Y, Ai J, Chen L, Li Y, Kwong DL, Fu L, Guan XY (2011) Characterization of tumor-suppressive function of SOX6 in human esophageal squamous cell carcinoma. Clin Cancer Res 17:46–55. https://doi.org/10.1158/1078-0432.Ccr-10-1155

    Article  CAS  PubMed  Google Scholar 

  23. Tsai YP, Wu KJ (2014) Epigenetic regulation of hypoxia-responsive gene expression: focusing on chromatin and DNA modifications. Int J Cancer 134:249–256. https://doi.org/10.1002/ijc.28190

    Article  CAS  PubMed  Google Scholar 

  24. Zheng X, Fan H, Liu Y, Wei Z, Li X, Wang A, Chen W, Lu Y (2022) Hypoxia boosts aerobic glycolysis in carcinoma: a complex process for tumour development. Curr Mol Pharmacol 15:487–501. https://doi.org/10.2174/1874467214666210811145752

    Article  CAS  PubMed  Google Scholar 

  25. Minton DR, Nam M, McLaughlin DJ, Shin J, Bayraktar EC, Alvarez SW, Sviderskiy VO, Papagiannakopoulos T, Sabatini DM, Birsoy K, Possemato R (2018) Serine Catabolism by SHMT2 Is required for proper mitochondrial translation initiation and maintenance of formylmethionyl-tRNAs. Mol Cell 69(610–621):e615. https://doi.org/10.1016/j.molcel.2018.01.024

    Article  CAS  Google Scholar 

  26. Paredes F, Williams HC, San Martin A (2021) Metabolic adaptation in hypoxia and cancer. Cancer Lett 502:133–142. https://doi.org/10.1016/j.canlet.2020.12.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Xu M, Wang P, Sun S, Gao L, Sun L, Zhang L, Zhang J, Wang S, Liang X (2020) Smart strategies to overcome tumor hypoxia toward the enhancement of cancer therapy. Nanoscale 12:21519–21533. https://doi.org/10.1039/d0nr05501h

    Article  CAS  PubMed  Google Scholar 

  28. Ren S, Liu J, Feng Y, Li Z, He L, Li L, Cao X, Wang Z, Zhang Y (2019) Knockdown of circDENND4C inhibits glycolysis, migration and invasion by up-regulating miR-200b/c in breast cancer under hypoxia. J Exp Clin Cancer Res 38:388. https://doi.org/10.1186/s13046-019-1398-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tian T, Dong Y, Zhu Y, Chen Y, Li X, Kuang Q, Liu X, Li P, Li J, Zhou L (2021) Hypoxia-induced CNPY2 upregulation promotes glycolysis in cervical cancer through activation of AKT pathway. Biochem Biophys Res Commun 551:63–70. https://doi.org/10.1016/j.bbrc.2021.02.116

    Article  CAS  PubMed  Google Scholar 

  30. Yang Q, Xu J, Gu J, Shi H, Zhang J, Zhang J, Chen ZS, Fang X, Zhu T, Zhang X (2022) Extracellular vesicles in cancer drug resistance: roles, mechanisms, and implications. Adv Sci (Weinh) 9:e2201609. https://doi.org/10.1002/advs.202201609

    Article  CAS  PubMed  Google Scholar 

  31. Abdollahi P, Vandsemb EN, Elsaadi S, Rost LM, Yang R, Hjort MA, Andreassen T, Misund K, Slordahl TS, Ro TB, Sponaas AM, Moestue S, Bruheim P, Borset M (2021) Phosphatase of regenerating liver-3 regulates cancer cell metabolism in multiple myeloma. FASEB J 35:e21344. https://doi.org/10.1096/fj.202001920RR

    Article  CAS  PubMed  Google Scholar 

  32. Tajan M, Hennequart M, Cheung EC, Zani F, Hock AK, Legrave N, Maddocks ODK, Ridgway RA, Athineos D, Suarez-Bonnet A, Ludwig RL, Novellasdemunt L, Angelis N, Li VSW, Vlachogiannis G, Valeri N, Mainolfi N, Suri V, Friedman A, Manfredi M, Blyth K, Sansom OJ, Vousden KH (2021) Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy. Nat Commun 12:366. https://doi.org/10.1038/s41467-020-20223-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang P, Yang Q (2021) Overexpression of SHMT2 predicts a poor prognosis and promotes tumor cell growth in bladder cancer. Front Genet 12:682856. https://doi.org/10.3389/fgene.2021.682856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Xie SY, Shi DB, Ouyang Y, Lin F, Chen XY, Jiang TC, Xia W, Guo L, Lin HX (2022) SHMT2 promotes tumor growth through VEGF and MAPK signaling pathway in breast cancer. Am J Cancer Res 12:3405–3421

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Woo CC, Chen WC, Teo XQ, Radda GK, Lee PT (2016) Downregulating serine hydroxymethyltransferase 2 (SHMT2) suppresses tumorigenesis in human hepatocellular carcinoma. Oncotarget 7:53005–53017. https://doi.org/10.18632/oncotarget.10415

    Article  PubMed  PubMed Central  Google Scholar 

  36. Liu Y, Yin C, Deng MM, Wang Q, He XQ, Li MT, Li CP, Wu H (2019) High expression of SHMT2 is correlated with tumor progression and predicts poor prognosis in gastrointestinal tumors. Eur Rev Med Pharmacol Sci 23:9379–9392. https://doi.org/10.26355/eurrev_201911_19431

    Article  CAS  PubMed  Google Scholar 

  37. Yu J, Chai P, Xie M, Ge S, Ruan J, Fan X, Jia R (2021) Histone lactylation drives oncogenesis by facilitating m(6)A reader protein YTHDF2 expression in ocular melanoma. Genome Biol 22:85. https://doi.org/10.1186/s13059-021-02308-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Miao Z, Zhao X, Liu X (2023) Hypoxia induced beta-catenin lactylation promotes the cell proliferation and stemness of colorectal cancer through the wnt signaling pathway. Exp Cell Res 422:113439. https://doi.org/10.1016/j.yexcr.2022.113439

    Article  CAS  PubMed  Google Scholar 

  39. Yi D, Yilihamu Y, Jiang C, Wang R, Lu X, Sang J, Su L (2022) MTHFD1L knockdown diminished cells growth in papillary thyroid cancer. Tissue Cell 77:101869. https://doi.org/10.1016/j.tice.2022.101869

    Article  CAS  PubMed  Google Scholar 

  40. Agarwal S, Behring M, Hale K, Al Diffalha S, Wang K, Manne U, Varambally S (2019) MTHFD1L, a folate cycle enzyme, is involved in progression of colorectal cancer. Transl Oncol 12:1461–1467. https://doi.org/10.1016/j.tranon.2019.07.011

    Article  PubMed  PubMed Central  Google Scholar 

  41. Eich ML, Rodriguez Pena MDC, Chandrashekar DS, Chaux A, Agarwal S, Gordetsky JB, Ferguson JE, Sonpavde GP, Netto GJ, Varambally S (2019) Expression and Role of Methylenetetrahydrofolate Dehydrogenase 1 Like (MTHFD1L) in Bladder Cancer. Transl Oncol 12:1416–1424. https://doi.org/10.1016/j.tranon.2019.07.012

    Article  PubMed  PubMed Central  Google Scholar 

  42. Yang YS, Yuan Y, Hu WP, Shang QX, Chen LQ (2018) The role of mitochondrial folate enzyme MTHFD1L in esophageal squamous cell carcinoma. Scand J Gastroenterol 53:533–540. https://doi.org/10.1080/00365521.2017.1407440

    Article  CAS  PubMed  Google Scholar 

  43. Zhou J, Yang Y, Cheng J, Luan S, Xiao X, Li X, Fang P, Gu Y, Shang Q, Zhang H, Chen L, Zeng X, Yuan Y (2023) MTHFD1L confers a poor prognosis and malignant phenotype in esophageal squamous cell carcinoma by activating the ERK5 signaling pathway. Exp Cell Res 427:113584. https://doi.org/10.1016/j.yexcr.2023.113584

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Thoracic Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157, West 5th Road, Xi’an, 710004, Shaanxi, China

    Zhe Qiao, Yu Li, Shaomin Li, Shiyuan Liu & Yao Cheng

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  1. Zhe Qiao
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  2. Yu Li
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  3. Shaomin Li
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  4. Shiyuan Liu
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Contributions

ZQ: designed the study and draft the manuscript. YL: collected the data and processed statistical data. SL: analyzed and interpreted the data. SL: partly contributed to the experiment. YC: reviewed, and revised the paper. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Yao Cheng.

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This study was approved by the Ethics Committee of The Second Affiliated Hospital of Xi'an Jiaotong University.

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Qiao, Z., Li, Y., Li, S. et al. Hypoxia-induced SHMT2 protein lactylation facilitates glycolysis and stemness of esophageal cancer cells. Mol Cell Biochem 479, 3063–3076 (2024). https://doi.org/10.1007/s11010-023-04913-x

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