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  • Targeting the oncogenic m6A demethylase FTO suppresses tumourigenesis and potentiates immune response in hepatocellular carcinoma

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Hepatology
Original research
Targeting the oncogenic m6A demethylase FTO suppresses tumourigenesis and potentiates immune response in hepatocellular carcinoma
  1. Ao Chen1,2,3,
  2. Vanilla Xin Zhang1,2,
  3. Qingyang Zhang1,2,
  4. Karen Man-Fong Sze1,2,
  5. Lu Tian1,2,
  6. Hongyang Huang1,2,
  7. Xia Wang1,2,
  8. Eva Lee1,2,
  9. Jingyi Lu1,2,
  10. Xueying Lyu1,2,
  11. Man-Fong Joyce Lee1,2,
  12. Chun Ming Wong1,2,
  13. Daniel Wai-Hung Ho1,2,
  14. Irene Oi-Lin Ng1,2
  1. 1 Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong
  2. 2 State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
  3. 3 Department of Biology, Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei Province, China
  1. Correspondence to Professor Irene Oi-Lin Ng, Department of Pathology, The University of Hong Kong, Hong Kong 0000, Hong Kong; iolng{at}hkucc.hku.hk

Abstract

Objective Fat mass and obesity-associated protein (FTO), an eraser of N 6-methyadenosine (m6A), plays oncogenic roles in various cancers. However, its role in hepatocellular carcinoma (HCC) is unclear. Furthermore, small extracellular vesicles (sEVs, or exosomes) are critical mediators of tumourigenesis and metastasis, but the relationship between FTO-mediated m6A modification and sEVs in HCC is unknown.

Design The functions and mechanisms of FTO and glycoprotein non-metastatic melanoma protein B (GPNMB) in HCC progression were investigated in vitro and in vivo. Neutralising antibody of syndecan-4 (SDC4) was used to assess the significance of sEV-GPNMB. FTO inhibitor CS2 was used to examine the effects on anti-PD-1 and sorafenib treatment.

Results FTO expression was upregulated in patient HCC tumours. Functionally, FTO promoted HCC cell proliferation, migration and invasion in vitro, and tumour growth and metastasis in vivo. FTO knockdown enhanced the activation and recruitment of tumour-infiltrating CD8+ T cells. Furthermore, we identified GPNMB to be a downstream target of FTO, which reduced the m6A abundance of GPNMB, hence, stabilising it from degradation by YTH N 6-methyladenosine RNA binding protein F2. Of note, GPNMB was packaged into sEVs derived from HCC cells and bound to the surface receptor SDC4 of CD8+ T cells, resulting in the inhibition of CD8+ T cell activation. A potential FTO inhibitor, CS2, suppresses the oncogenic functions of HCC cells and enhances the sensitivity of anti-PD-1 and sorafenib treatment.

Conclusion Targeting the FTO/m6A/GPNMB axis could significantly suppress tumour growth and metastasis, and enhance immune activation, highlighting the potential of targeting FTO signalling with effective inhibitors for HCC therapy.

  • HEPATOCELLULAR CARCINOMA
  • IMMUNE RESPONSE
  • CELL BIOLOGY
  • GENE REGULATION

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/gutjnl-2024-331903

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • AC and VXZ contributed equally.

    • Contributors AC, VXZ and IO-LN provided the study concept and design. AC, VXZ and IO-LN wrote the manuscript. AC, VXZ, QZ, DW-HH, XL, CMW and IO-LN interpreted and analysed the data. AC, VXZ, KM-FS, LT, HH, XW, EL, JL, MFJL performed the experiments. IO-LN and MFJL collected the patients’ samples. LT and XW advised on extracellular vesicle-related experiments. IO-LN provided financial support. IO-LN is responsible for the overall content as the guarantor and supervised the project. All authors approved the final version of the manuscript.

    • Funding This project was supported in part by grants from the Research Grants Council of Hong Kong—Theme-based Research Scheme (T12-716/22R), Innovation and Technology Commission grant of Hong Kong SAR Government to State Key Laboratory of Liver Research (ITC PD/17-9), National Natural Science Foundation of China (82394451) and University Development Fund of The University of Hong Kong. IOLN is Loke Yew Professor in Pathology. AC is a Hong Kong Scholar.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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