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