Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

N6-methyladenosine demethyltransferase FTO mediated m6A modification of estrogen receptor alpha in non-small cell lung cancer tumorigenesis

Oncogene volume 43, pages 1288–1302 (2024)Cite this article

Subjects

Abstract

Fat mass and obesity-associated protein (FTO), which is closely linked with obesity and dietary intake, plays an important role in diet-related metabolic diseases. However, the underlying mechanism of the N6-methyladenosine (m6A) demethyltransferase FTO in tumor development and progression remains largely unexplored. Here, we demonstrated that FTO expression was largely lower in non-small cell lung cancer (NSCLC) samples than in adjacent healthy tissues, and its expression negatively correlated with poor prognosis. Gain- and loss-of-function assays revealed that FTO inhibited NSCLC tumor cell growth and metastasis in vitro and in vivo. Mechanistically, estrogen receptor alpha (ESR1) is a target of FTO, and increased FTO expression significantly impaired the m6A levels of ESR1 mRNA. There were two clear m6A modification sites (5247A and 5409A) in the 3′ untranslated region (3ʹUTR) of ESR1, and FTO could decrease their methylation. Moreover, the m6A readers YTHDF1 and IGF2BP3 recognized and bound the m6A sites in ESR1 mRNA, thereby enhancing its stability and facilitating tumor growth. We also showed that ESR1 has good diagnostic value for NSCLC. In conclusion, we uncovered an important mechanism of epitranscriptomic regulation by the FTO-YTHDF1-IGF2BP3-ESR1 axis and identified the potential of m6A-dependent therapeutic strategies for NSCLC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Low FTO expression correlated with poor clinical prognosis for non-small cell lung cancer patients.
Fig. 2: FTO inhibited NSCLC cell growth and metastasis in vitro and in vivo.
Fig. 3: FTO mediated ESR1 mRNA m6A modification and regulated ESR1 mRNA stability.
Fig. 4: ESR1 mRNA is a target of m6A reader YTHDF1 and IGF2BP3.
Fig. 5: ESR1 promoted NSCLC tumor growth via YTHDF1 and IGF2BP3 in vitro and in vivo.
Fig. 6: The clinical significance of the FTO-YTHDF1-IGF2BP3-ESR1 axis in NSCLC and its correlation with disease status.
Fig. 7: The roles of the FTO-m6A-YTHDF1-IGF2BP3-ESR1 axis in promoting NSCLC tumor progression.

Similar content being viewed by others

Data availability

Source data are available from the corresponding author upon reasonable request.

References

  1. Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR. Comprehensive analysis of mRNA methylation reveals enrichment in 3’ UTRs and near stop codons. Cell. 2012;149:1635–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Huang H, Weng H, Chen J. m6A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell. 2020;37:270–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Liu X, Feng M, Hao X, Gao Z, Wu Z, Wang Y, et al. m6A methylation regulates hypoxia-induced pancreatic cancer glycolytic metabolism through ALKBH5-HDAC4-HIF1α positive feedback loop. Oncogene. 2023;42:2047–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Niu X, Yang Y, Ren Y, Zhou S, Mao Q, Wang Y. Crosstalk between m6A regulators and mRNA during cancer progression. Oncogene. 2022;41:4407–19.

    Article  CAS  PubMed  Google Scholar 

  5. An Y, Duan H. The role of m6A RNA methylation in cancer metabolism. Mol Cancer. 2022;21:14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Deng X, Su R, Weng H, Huang H, Li Z, Chen J. RNA N6-methyladenosine modification in cancers: current status and perspectives. Cell Res. 2018;28:507–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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 

  8. Zheng G, Dahl J, Niu Y, Fedorcsak P, Huang C, Li C, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol cell. 2013;49:18–29.

    Article  CAS  PubMed  Google Scholar 

  9. Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, et al. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther. 2021;6:74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yan H, Zhang L, Cui X, Zheng S, Li R. Roles and mechanisms of the m6A reader YTHDC1 in biological processes and diseases. Cell Death Discov. 2022;8:237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Deng LJ, Deng WQ, Fan SR, Chen MF, Qi M, Lyu WY, et al. m6A modification: recent advances, anticancer targeted drug discovery and beyond. Mol Cancer. 2022;21:52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tung YCL, Yeo Giles SH, O’Rahilly S, Coll Anthony P. Obesity and FTO: changing focus at a complex locus. Cell Metab. 2014;20:710–8.

    Article  CAS  PubMed  Google Scholar 

  13. Lin Z, Wan AH, Sun L, Liang H, Niu Y, Deng Y, et al. N6-methyladenosine demethylase FTO enhances chemo-resistance in colorectal cancer through SIVA1-mediated apoptosis. Mol Ther. 2023;31:517–34.

    Article  CAS  PubMed  Google Scholar 

  14. Li Y, Su R, Deng X, Chen Y, Chen J. FTO in cancer: functions, molecular mechanisms, and therapeutic implications. Trends in Cancer. 2022;8:598–614.

    Article  PubMed  Google Scholar 

  15. Tao L, Mu X, Chen H, Jin D, Zhang R, Zhao Y, et al. FTO modifies the m6A level of MALAT and promotes bladder cancer progression. Clin Transl Med. 2021;11:e310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhou Y, Wang Q, Deng H, Xu B, Zhou Y, Liu J, et al. N6-methyladenosine demethylase FTO promotes growth and metastasis of gastric cancer via m6A modification of caveolin-1 and metabolic regulation of mitochondrial dynamics. Cell Death Dis. 2022;13:72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Huang J, Sun W, Wang Z, Lv C, Zhang T, Zhang D, et al. FTO suppresses glycolysis and growth of papillary thyroid cancer via decreasing stability of APOE mRNA in an N6-methyladenosine-dependent manner. J Exp Clin Cancer Res. 2022;41:42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tan Z, Shi S, Xu J, Liu X, Lei Y, Zhang B, et al. RNA N6-methyladenosine demethylase FTO promotes pancreatic cancer progression by inducing the autocrine activity of PDGFC in an m6A-YTHDF2-dependent manner. Oncogene. 2022;41:2860–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Grinshpun A, Chen V, Sandusky ZM, Fanning SW, Jeselsohn R. ESR1 activating mutations: from structure to clinical application. Biochim Biophys Acta Rev Cancer. 2023;1878:188830.

    Article  PubMed  Google Scholar 

  20. Li Z, Wu Y, Yates ME, Tasdemir N, Bahreini A, Chen J, et al. Hotspot ESR1 mutations are multimodal and contextual modulators of breast cancer metastasis. Cancer Res. 2022;82:1321–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23:85.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Huang Y-M, Wang W, Hsieh P-P, Chen H-H. Haplotype of ESR1 and PPARD genes is associated with higher anthropometric changes in Han Chinese obesity by adjusting dietary factors-an 18-month follow-up. Nutrients. 2022;14:4425.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Nakada D, Oguro H, Levi BP, Ryan N, Kitano A, Saitoh Y, et al. Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy. Nature. 2014;505:555–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Deng X, Qing Y, Horne D, Huang H, Chen J. The roles and implications of RNA m6A modification in cancer. Nat Rev Clin Oncol. 2023;20:507–26.

    Article  CAS  PubMed  Google Scholar 

  25. Zeng L, Huang X, Zhang J, Lin D, Zheng J. Roles and implications of mRNA N6‐methyladenosine in cancer. Cancer Commun (Lond). 2023;43:729–48.

    Article  PubMed  Google Scholar 

  26. Ma L, Xue X, Zhang X, Yu K, Xu X, Tian X, et al. The essential roles of m6A RNA modification to stimulate ENO1-dependent glycolysis and tumorigenesis in lung adenocarcinoma. J Exp Clin Cancer Res. 2022;41:36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ma L, Chen T, Zhang X, Miao Y, Tian X, Yu K, et al. The m6A reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function. Redox Biol. 2021;38:101801.

    Article  CAS  PubMed  Google Scholar 

  28. Burns KA, Korach KS. Estrogen receptors and human disease: an update. Arch Toxicol. 2012;86:1491–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. El-Botty R, Morriset L, Montaudon E, Tariq Z, Schnitzler A, Bacci M, et al. Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers. Nat Commun. 2023;14:4221.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Li A, Chen YS, Ping XL, Yang X, Xiao W, Yang Y, et al. Cytoplasmic m6A reader YTHDF3 promotes mRNA translation. Cell Res. 2017;27:444–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  32. Yang Y, Hsu PJ, Chen YS, Yang YG. Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res. 2018;28:616–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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 

  34. Shi H, Wei J, He C. Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell. 2019;74:640–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xu X, Cui J, Wang H, Ma L, Zhang X, Guo W, et al. IGF2BP3 is an essential N6-methyladenosine biotarget for suppressing ferroptosis in lung adenocarcinoma cells. Mater Today Bio. 2022;17:100503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Burstein HJ, DeMichele A, Somerfield MR, Henry NL. Testing for ESR1 mutations to guide therapy for hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer: ASCO guideline rapid recommendation update. J Clin Oncol. 2023;41:3423–5.

    Article  CAS  PubMed  Google Scholar 

  37. Gou X, Kim BJ, Anurag M, Lei JT, Young MN, Holt MV, et al. Kinome reprogramming is a targetable vulnerability in ESR1 fusion-driven breast cancer. Cancer Res. 2023;83:3237–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Liu J, Eckert MA, Harada BT, Liu S-M, Lu Z, Yu K, et al. m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer. Nat Cell Biol. 2018;20:1074–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chang G, Shi L, Ye Y, Shi H, Zeng L, Tiwary S, et al. YTHDF3 induces the translation of m6A-enriched gene transcripts to promote breast cancer brain metastasis. Cancer Cell. 2020;38:857–71.e857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shen C, Sheng Y, Zhu AC, Robinson S, Jiang X, Dong L, et al. RNA demethylase ALKBH5 selectively promotes tumorigenesis and cancer stem cell self-renewal in acute myeloid leukemia. Cell Stem Cell. 2020;27:64–80.e69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Frye M, Harada BT, Behm M, He C. RNA modifications modulate gene expression during development. Science. 2018;361:1346–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chen H, Pan Y, Zhou Q, Liang C, Wong C-C, Zhou Y, et al. METTL3 inhibits antitumor immunity by targeting m6A-BHLHE41-CXCL1/CXCR2 axis to promote colorectal cancer. Gastroenterology. 2022;163:891–907.

    Article  CAS  PubMed  Google Scholar 

  43. Ni Z, Sun P, Zheng J, Wu M, Yang C, Cheng M, et al. JNK signaling promotes bladder cancer immune escape by regulating METTL3-mediated m6A modification of PD-L1 mRNA. Cancer Res. 2022;82:1789–802.

    Article  CAS  PubMed  Google Scholar 

  44. Li Z-X, Zheng Z-Q, Yang P-Y, Lin L, Zhou G-Q, Lv J-W, et al. WTAP-mediated m6A modification of lncRNA DIAPH1-AS1 enhances its stability to facilitate nasopharyngeal carcinoma growth and metastasis. Cell Death Differ. 2022;29:1137–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rong D, Wu F, Lu C, Sun G, Shi X, Chen X, et al. m6A modification of circHPS5 and hepatocellular carcinoma progression through HMGA2 expression. Mol Ther Nucleic Acids. 2021;26:637–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Deng D, You A, Tian W, Yuan H, Gu L, Zhou J. TTC22 promotes m6A-mediated WTAP expression and colon cancer metastasis in an RPL4 binding-dependent pattern. Oncogene. 2022;41:3925–38.

    Article  PubMed  Google Scholar 

  47. Yu H, Zhao K, Zeng H, Li Z, Chen K, Zhang Z, et al. N6-methyladenosine (m6A) methyltransferase WTAP accelerates the Warburg effect of gastric cancer through regulating HK2 stability. Biomed Pharmacother. 2021;133:111075.

    Article  PubMed  Google Scholar 

  48. Sheng Y, Wei J, Yu F, Xu H, Yu C, Wu Q, et al. A critical role of nuclear m6A reader YTHDC1 in leukemogenesis by regulating MCM complex-mediated DNA replication. Blood. 2021;138:2838–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu T, Wei Q, Jin J, Luo Q, Liu Y, Yang Y, et al. The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic Acids Res. 2020;48:3816–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang L, Wan Y, Zhang Z, Jiang Y, Gu Z, Ma X, et al. IGF2BP1 overexpression stabilizes PEG10 mRNA in an m6A-dependent manner and promotes endometrial cancer progression. Theranostics. 2021;11:1100–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49:18–29.

    Article  CAS  PubMed  Google Scholar 

  52. Gerken T, Girard CA, Tung Y-CL, Webby CJ, Saudek V, Hewitson KS, et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007;318:1469–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Duan X, Yang L, Wang L, Liu Q, Zhang K, Liu S, et al. m6A demethylase FTO promotes tumor progression via regulation of lipid metabolism in esophageal cancer. Cell Biosci. 2022;12:60.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Cui Y, Zhang C, Ma S, Li Z, Wang W, Li Y, et al. RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma. J Exp Clin Cancer Res. 2021;40:294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Angus L, Beije N, Jager A, Martens JWM, Sleijfer S. ESR1 mutations: Moving towards guiding treatment decision-making in metastatic breast cancer patients. Cancer Treat Rev. 2017;52:33–40.

    Article  CAS  PubMed  Google Scholar 

  56. Li Z, McGinn O, Wu Y, Bahreini A, Priedigkeit NM, Ding K, et al. ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation. Nat Commun. 2022;13:2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shen M, Li Y, Wang Y, Shao J, Zhang F, Yin G, et al. N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells. Redox Biol. 2021;47:102151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, et al. Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20:285–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hu X, Nadalin G, De Luise M, Martin T, Wakeling A, Huggins R, et al. Circumvention of doxorubicin resistance in multi-drug resistant human leukaemia and lung cancer cells by the pure antioestrogen ICI 164384. Eur J Cancer. 1991;27:773–7.

    Article  CAS  PubMed  Google Scholar 

  60. Xu X, Ma L, Zhang X, Guo S, Guo W, Wang Y, et al. A positive feedback circuit between RN7SK snRNA and m6A readers is essential for tumorigenesis. Mol Ther. 2023;31:1615–35.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Natural Science Foundation of China (82273139, 82303043), Shanghai Science and Technology Committee Rising-Star Program (22QA1408300), Excellent Talents Nurture Project of Shanghai Chest Hospital (2021YNZYY02, 2021YNZYY01, 2021YNZYJ01), and the Talent Training Plan of Shanghai Chest Hospital in 2022 (RC-202301-130), The Nurture Projects for Basic Research of Shanghai Chest Hospital (2022YNJCQ08).

Author information

Author notes

  1. These authors contributed equally: Xin Xu, Shiyu Qiu, Bingjie Zeng.

Authors and Affiliations

  1. Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China

    Xin Xu, Bingjie Zeng, Yiwen Huang, Xianzhao Wang, Fusheng Li, Yiran Yang, Leiqun Cao, Jiayi Wang & Lifang Ma

  2. Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China

    Xin Xu, Shiyu Qiu, Yiwen Huang, Xiao Zhang, Jiayi Wang & Lifang Ma

Authors
  1. Xin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shiyu Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bingjie Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yiwen Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xianzhao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fusheng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yiran Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Leiqun Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jiayi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lifang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LM and JW conceived and designed the experiments; LM, JW and XZ developed the methodology; SQ, BZ and YH collected clinical samples and information; XX, XW, FL, YY, LC and XZ performed analysis of data and statistical; XX, BZ, CL and SQ were responsible for animal experiment; LM, JW and XZ supervised the study; LM and XX wrote, reviewed and revised the manuscript; LM, JW, XZ, XX and BZ provided financial support. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiao Zhang, Jiayi Wang or Lifang Ma.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All the animal experiments and collection of specimens were approved by the ethical committee of the Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, X., Qiu, S., Zeng, B. et al. N6-methyladenosine demethyltransferase FTO mediated m6A modification of estrogen receptor alpha in non-small cell lung cancer tumorigenesis. Oncogene 43, 1288–1302 (2024). https://doi.org/10.1038/s41388-024-02992-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-024-02992-8

Search

Advanced search

Quick links