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N6-methyladenosine demethyltransferase FTO-mediated autophagy in malignant development of oral squamous cell carcinoma

Oncogene volume 40, pages 3885–3898 (2021)Cite this article

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Abstract

N6-methyladenosine (m6A) is the most abundant internal mRNA modification in eukaryotes and plays an important role in tumorigenesis. However, the underlying mechanism remains largely unclear. Here, we established a cell model of rapamycin-induced autophagy to screen m6A-modifying enzymes. We found that m6A demethylase fat mass and obesity-associated protein (FTO) plays a key role in regulating autophagy and tumorigenesis by targeting the gene encoding eukaryotic translation initiation factor gamma 1 (eIF4G1) in oral squamous cell carcinoma (OSCC). Knocked down of FTO expression in OSCC cell lines, resulting in downregulation of eIF4G1 along with enhanced autophagic flux and inhibition of tumorigenesis. Rapamycin inhibited FTO activity, and directly targeted eIF4G1 transcripts and mediated their expression in an m6A-dependent manner. Dual-luciferase reporter and mutagenesis assays confirmed that YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2) targets eIF4G1. Conclusively, after FTO silencing, YTHDF2 captured eIF4G1 transcripts containing m6A, resulting in mRNA degradation and decreased expression of eIF4G1 protein, thereby promoting autophagy and reducing tumor occurrence. Therefore, rapamycin may regulate m6A levels, determining the autophagic flux of OSCC, thereby affecting the biological characteristics of cancer cells. This insight expands our understanding of the crosstalk between autophagy and RNA methylation in tumorigenesis, which is essential for therapeutic strategy development for OSCC.

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Fig. 1: FTO expression is elevated in OSCC tissues and inhibited by rapamycin.
Fig. 2: Downregulation of FTO enhances the autophagic flux and decreases the proliferation, migration, and invasion of OSCC cells.
Fig. 3: eIF4G1 is involved in m6A-regulated autophagy in cancer cells.
Fig. 4: Downregulation of eIF4G1 expression enhances autophagic flux and decreases the proliferation, migration, and invasion of OSCC cells.
Fig. 5: Correlation of the expression levels of FTO and eIF4G1 in vivo.
Fig. 6: A proposed model for the critical link between FTO and autophagy in rapamycin-treated OSCC cells.

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References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics 2012. CA Cancer J Clin. 2015;65:87–108.

    Article  PubMed  Google Scholar 

  2. Krishna Rao SV, Mejia G, Roberts-Thomson K, Logan R. Epidemiology of oral cancer in Asia in the past decade-an update (2000–2012). Asian Pac J Cancer Prev. 2013;14:5567–677.

    Article  PubMed  Google Scholar 

  3. Mel M, Shanti RM. Evaluation and staging of oral cancer. Dent Clin North Am. 2018;62:47–58.

    Article  Google Scholar 

  4. Kademani D, Bell RB, Schmidt BL, Blanchaert R, Fernandes R, Lambert P, et al. Oral and maxillofacial surgeons treating oral cancer: a preliminary report from the American Association of Oral and Maxillofacial Surgeons Task Force on Oral Cancer. J Oral Maxillofac Surg. 2008;66:2151–7.

    Article  PubMed  Google Scholar 

  5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  6. Diao P, Wu Y, Li J, Zhang W, Huang R, Zhou C, et al. Preoperative systemic immune-inflammation index predicts prognosis of patients with oral squamous cell carcinoma after curative resection. Transl Med. 2018;16:365.

    Article  CAS  Google Scholar 

  7. Zanoni DK, Montero PH, Migliacci JC, Shah JP, Wong RJ, Ganly I, et al. Survival outcomes after treatment of cancer of the oral cavity (1985–2015). Oral Oncol. 2019;90:115–21.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kao YY, Chou CH, Yeh LY, Chen YF, Chang KW, Liu CJ, et al. MicroRNA miR-31 targets SIRT3 to disrupt mitochondrial activity and increase oxidative stress in oral carcinoma. Cancer Lett. 2019;456:40–48.

    Article  CAS  PubMed  Google Scholar 

  9. Liu L, Wu Y, Li Q, Liang J, He Q, Zhao L, et al. METTL3 promotes tumorigenesis and metastasis through BMI1 m6A methylation in oral squamous cell carcinoma. Mol Ther. 2020;28:2177–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Stolz A, Ernst A, Dikic I. Cargo recognition and trafficking in selective autophagy. Nat Cell Biol. 2014;16:495–1.

    Article  CAS  PubMed  Google Scholar 

  11. Green DR, Levine B. To be or not to be? How selective autophagy and cell death govern cell fate. Cell. 2014;157:65–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kroemer G, Mariño G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40:280–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yonekawa T, Thorburn A. Autophagy and cell death. Essays Biochem. 2013;55:105–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mowers EE, Sharifi MN, Macleod KF. Autophagy in cancer metastasis. Oncogene 2017;36:1619–30.

    Article  CAS  PubMed  Google Scholar 

  15. Jacob JA, Salmani JMM, Jiang Z, Feng L, Song J, Jia X, et al. Autophagy: an overview and its roles in cancer and obesity. Clin Chim Acta. 2017;468:85–9.

    Article  CAS  PubMed  Google Scholar 

  16. Weng J, Wang C, Wang Y, Tang H, Liang J, Liu X, et al. Beclin1 inhibits proliferation, migration and invasion in tongue squamous cell carcinoma cell lines. Oral Oncol. 2014;50:983–90.

    Article  CAS  PubMed  Google Scholar 

  17. Chen G, Zhang Y, Liang J, Li W, Zhu Y, Zhang M, et al. Deregulation of hexokinase II is associated with glycolysis, autophagy, and the epithelial-mesenchymal transition in tongue squamous cell carcinoma under hypoxia. Biomed Res. Int. 2018;2018:8480762.

    PubMed  PubMed Central  Google Scholar 

  18. Cui Q, Shi H, Ye P, Li L, Qu Q, Sun G, et al. m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep. 2017;18:2622–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lin S, Choe J, Du P, Triboulet R, Gregory RI. The m6A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell. 2016;62:335–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cai X, Wang X, Cao C, Gao Y, Zhang S, Yang Z, et al. HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g. Cancer Lett. 2018;415:11–9.

    Article  CAS  PubMed  Google Scholar 

  21. Chen M, Wei L, Law CT, Tsang FH, Shen J, Cheng CL, et al. RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology. 2018;67:2254–70.

    Article  CAS  PubMed  Google Scholar 

  22. Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, et al. FTO plays an oncogenic role in acute myeloid leukemia as a N6-methyladenosine RNA demethylase. Cancer Cell. 2017;31:127–41.

    Article  PubMed  Google Scholar 

  23. Zhao W, Qi X, Liu L, Liu Z, Ma S, Wu J. Epigenetic regulation of m6A modifications in human cancer. Mol Ther Nucleic Acids. 2020;19:405–12.

    Article  CAS  PubMed  Google Scholar 

  24. Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, et al. N6-methyladenosine dependent regulation of messenger RNA stability. Nature. 2014;505:117–20.

    Article  PubMed  Google Scholar 

  25. Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, et al. N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161:1388–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7:885–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jin S, Zhang X, Miao Y, Liang P, Zhu K, She Y, et al. m6A RNA modification controls autophagy through upregulating ULK1 protein abundance. Cell Res. 2018;28:955–7.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Gulati P, Cheung MK, Antrobus R, Church CD, Harding HP, Tung YC, et al. Role for the obesity-related FTO gene in the cellular sensing of amino acids. Proc Natl Acad Sci USA. 2013;110:2557–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hale CM, Cheng Q, Ortuno D, Huang M, Nojima D, Kassner PD, et al. Identification of modulators of autophagic flux in an image-based high content siRNA screen. Autophagy. 2016;12:713–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ramírez-Valle F, Braunstein S, Zavadil J, Formenti SC, Schneider RJ. eIF4G1 links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy. J Cell Biol. 2008;181:293–7.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Zhou J, Wan J, Gao X, Zhang X, Jaffrey SR, Qian SB. Dynamic m6A mRNA methylation directs translational control of heat shock response. Nature. 2015;526:591–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Klionsky DJ, Abeliovich H, Agostinis P, Agrawal DK, Aliev G, Askew DS, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy. 2008;4:151–75.

    Article  CAS  PubMed  Google Scholar 

  33. Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J Biol Chem. 2010;285:13107–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Parihar M, Dodds SG, Hubbard G, Javors MA, Strong R, Hasty P et al. Rapamycin extends life span in ApcMin/+ colon cancer FAP model. Clin Colorectal Cancer. 2020; e-pub ahead of print 15 September 2020; https://doi.org/10.1016/j.clcc.2020.08.006.

  35. Xia Q, Xu M, Zhang P, Liu L, Meng X, Dong L. Therapeutic potential of autophagy in glioblastoma treatment with phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway inhibitors. Front Oncol. 2020;10:572904.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Zhu X, Xu A, Zhang Y, Huo N, Cong R, Ma L, et al. ITPKA1 promotes growth, migration and invasion of renal cell carcinoma via activation of mTOR signaling pathway. Onco Targets Ther. 2020;13:10515–10123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fang YJ, Jiang P, Zhai H, Dong JS. LncRNA GAS8-AS1 inhibits ovarian cancer progression through activating Beclin1-mediated autophagy. Onco Targets Ther. 2020;13:10431–1040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Day TA, Shirai K, O’Brien PE, Matheus MG, Godwin K, Sood AJ, et al. Inhibition of mTOR signaling and clinical activity of rapamycin in head and neck cancer in a window of opportunity trial. Clin Cancer Res. 2019;25:1156–64.

    Article  CAS  PubMed  Google Scholar 

  39. Towers CG, Thorburn A. Therapeutic targeting of autophagy. EBioMedicine. 2016;14:15–23.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Liu L, He J, Wei X, Wan G, Lao Y, Xu W, et al. MicroRNA-20a-mediated loss of autophagy contributes to breast tumorigenesis by promoting genomic damage and instability. Oncogene. 2017;36:5874–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Won KY, Kim GY, Kim YW, Song JY, Lim SJ. Clinicopathologic correlation of beclin-1 and bcl-2 expression in human breast cancer. Hum Pathol. 2010;41:107–12.

    Article  CAS  PubMed  Google Scholar 

  42. Shen Y, Li DD, Wang LL, Deng R, Zhu XF. Decreased expression of autophagyrelated proteins in malignant epithelial ovarian cancer. Autophagy. 2008;4:1067–8.

    Article  CAS  PubMed  Google Scholar 

  43. Chen YB, Hou JH, Feng XY, Chen S, Zhou ZW, Zhang XS, et al. Decreased expression of Beclin 1 correlates with a metastatic phenotypic feature and adverse prognosis of gastric carcinomas. J Surg Oncol. 2012;105:542–7.

    Article  CAS  PubMed  Google Scholar 

  44. Zhao Z, Zhao J, Xue J, Zhao X, Liu P. Autophagy inhibition promotes epithelial-mesenchymal transition through ROS/HO-1 pathway in ovarian cancer cells. Am J Cancer Res. 2016;6:2162–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Schaefer L, Tredup C, Gubbiotti MA, Iozzo RV. Proteoglycan neofunctions: regulation of inflammation and autophagy in cancer biology. FEBS J. 2017;284:10–26.

    Article  CAS  PubMed  Google Scholar 

  46. Li Y, Zheng D, Wang F, Xu Y, Yu H, Zhang H. Expression of demethylase genes, FTO and ALKBH1, is associated with prognosis of gastric cancer. Dig Dis Sci. 2019;64:1503–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cheung MK, Gulati P, O’Rahilly S, Yeo GS. FTO expression is regulated by availability of essential amino acids. Int J Obes. 2013;37:744–7.

    Article  CAS  Google Scholar 

  48. Wang X, Wu R, Liu Y, Zhao Y, Bi Z, Yao Y. m6A mRNA methylation controls autophagy and adipogenesis by targeting Atg5 and Atg7. Autophagy. 2020;16:1221–35.

    Article  CAS  PubMed  Google Scholar 

  49. Jackson RJ, Hellen CU, Pestova TV. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol. 2010;11:113–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Fatscher T, Boehm V, Weiche B, Gehring NH. The interaction of cytoplasmic poly(A)-binding protein with eukaryotic initiation factor 4G suppresses nonsense-mediated mRNA decay. RNA 2014;20:1579–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dell’Anno I, Barbarino M, Barone E, Giordano A, Luzzi L, Bottaro M, et al. eIF4G1 and as possible drivers for malignant pleural mesothelioma. Int J Mol Sci. 2020;21:4856.

    Article  PubMed Central  Google Scholar 

  52. Park EH, Walker SE, Lee JM, Rothenburg S, Lorsch JR, Hinnebusch AG. Multiple elements in the eIF4G1 N-terminus promote assembly of eIF4G1•PABP mRNPs in vivo. EMBO J. 2011;30:302–16.

    Article  CAS  PubMed  Google Scholar 

  53. Jaiswal PK, Koul S, Palanisamy N, Koul HK. Eukaryotic translation initiation factor 4 gamma 1 (eIF4G1): a target for cancer therapeutic intervention? Cancer Cell Int. 2019;19:224.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Fang W, Li X, Jiang Q, Liu Z, Yang H, Wang S, et al. Transcriptional patterns, biomarkers and pathways characterizing nasopharyngeal carcinoma of Southern China. J Transl Med. 2008;6:32.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Tu L, Liu Z, He X, He Y, Yang H, Jiang Q, et al. Over-expression of eukaryotic translation initiation factor 4 gamma 1 correlates with tumor progression and poor prognosis in nasopharyngeal carcinoma. Mol Cancer. 2010;9:78.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Comtesse N, Keller A, Diesinger I, Bauer C, Kayser K, Huwer H, et al. Frequent overexpression of the genes FXR1, CLAPM1 and EIF4G located on amplicon 3q26-27 in squamous cell carcinoma of the lung. Int J Cancer. 2007;120:2538–2544.

    Article  CAS  PubMed  Google Scholar 

  57. Cao Y, Wei M, Li B, Liu Y, Lu Y, Tang Z, et al. Functional role of eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) in NSCLC. Oncotarget. 2016;7:24242–51.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Braunstein S, Karpisheva K, Pola C, Goldberg J, Hochman T, Yee H, et al. A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer. Mol Cell. 2007;28:501–12.

    Article  CAS  PubMed  Google Scholar 

  59. Gassen NC, Niemeyer D, Muth D, Corman VM, Martinelli S, Gassen A, et al. SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection. Nat Commun. 2019;10:5770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Chen Q, Xie W, Kuhn DJ, Voorhees PM, Lopez-Girona A, Mendy D, et al. Targeting the p27 E3 ligase SCF(Skp2) results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy. Blood. 2008;111:4690–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yang S, Wei J, Cui YH, Park G, Shah P, Deng Y, et al. m6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade. Nat Commun. 2019;10:2782.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Li J, Xie H, Ying Y, Chen H, Yan H, He L, et al. YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer. Mol Cancer. 2020;19:152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ke S, Alemu EA, Mertens C, Gantman EC, Fak JJ, Mele A, et al. A majority of m6A residues are in the last exons, allowing the potential for 3′UTR regulation. Genes Dev. 2015;29:2037–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lin X, Chai G, Wu Y, Li J, Chen F, Liu J, et al. RNA m6A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. Nat Commun. 2019;10:2065.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Ho AS, Kim S, Tighiouart M, Gudino C, Mita A, Scher KS, et al. Metastatic lymph node burden and survival in oral cavity cancer. J Clin Oncol. 2017;35:3601–9.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Cai H, Li J, Zhang Y, Liao Y, Zhu Y, Wang C, et al. LDHA promotes oral squamous cell carcinoma progression through facilitating glycolysis and epithelial– mesenchymal transition. Front Oncol. 2019;9:1446.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81874128 and 82072994); Sun Yat-sen University Clinical Research 5010 Program (Grant No. 2015018).

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  1. These authors contributed equally: Fang Wang, Yan Liao, Ming Zhang

Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

    Fang Wang, Yan Liao, Ming Zhang, Yue Zhu, Wenjin Wang, Hongshi Cai, Jianfeng Liang, Fan Song, Chen Hou, Shuojin Huang, Yadong Zhang, Cheng Wang & Jinsong Hou

  2. Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China

    Fang Wang, Yan Liao, Ming Zhang, Yue Zhu, Wenjin Wang, Hongshi Cai, Jianfeng Liang, Fan Song, Chen Hou, Shuojin Huang, Yadong Zhang, Cheng Wang & Jinsong Hou

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Wang, F., Liao, Y., Zhang, M. et al. N6-methyladenosine demethyltransferase FTO-mediated autophagy in malignant development of oral squamous cell carcinoma. Oncogene 40, 3885–3898 (2021). https://doi.org/10.1038/s41388-021-01820-7

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