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Methyltransferase like 3 inhibition limits intrahepatic cholangiocarcinoma metabolic reprogramming and potentiates the efficacy of chemotherapy

Oncogene volume 42, pages 2507–2520 (2023)Cite this article

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Abstract

N6-methyladenosine (m6A) RNA methylation and its associated methyltransferase like 3 (METTL3) are involved in the development and maintenance of various tumors. The present study aimed to evaluate the cross-talk of METTL3 with glucose metabolism and reveal a novel mechanism for intrahepatic cholangiocarcinoma (ICC) progression. Real-time quantitative PCR, western blotting, and immunohistochemistry analyses suggested that METTL3 was highly expressed in ICC, which was correlated with poor patient prognosis. Immunoprecipitation sequencing of m6A-RNA showed that METTL3 upregulated m6A modification of NFAT5, which recruited IGF2BP1 for NFAT5 mRNA stabilization. Elevated expression of NFAT5 increased the expression of the gluconeogenesis-related genes GLUT1 and PGK1, resulting in enhanced aerobic glycolysis, proliferation, and tumor metastasis of ICC. Moreover, higher METTL3 expression was observed in tumor tissues of ICC patients with activated ICC glucose metabolism. Importantly, STM2457, a highly potent METTL3 inhibitor, which inhibited METTL3 activity and acted synergistically with gemcitabine, suggests that reprogramming RNA epigenetic modifications may serve as a potential therapeutic strategy. Overall, our findings highlighted the role of METTL3-mediated m6A modification of NFAT5 in activating glycolytic reprogramming in ICC and proposed that the METTL3/NFAT5 axis was a clinical target for the management of ICC chemoresistance by targeting cancer glycolysis.

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Fig. 1: METTL3 is overexpressed in ICC and correlated with poor prognosis.
Fig. 2: METTL3 promotes ICC proliferation in vitro and in vivo.
Fig. 3: Transcriptome sequencing and m6A sequencing identified NFAT5 as a downstream gene of METTL3.
Fig. 4: NFAT5 mRNA stability is regulated via an m6A-IGF2BP1-dependent pathway.
Fig. 5: METTL3 promotes ICC malignant process via upregulating NFAT5 expression.
Fig. 6: METTL3-NFAT5 axis accelerates glycolysis by targeting GLUT1 and PGK1.
Fig. 7: METTL3 blockade enhances chemotherapeutic efficacy against ICC.
Fig. 8: Clinical significance of the METTL3/NFAT5/GLUT1/PGK1 axis in ICC patient samples.

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All relevant data are within the paper and its supplementary files.

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Acknowledgements

We thank Charlesworth Author Services for the professional editing of the paper.

Funding

Shanghai Municipal Science and Technology Major Project (Grant No. 2018SHZDZX05). National Key Research and Development Program of China (2018YFC1312100 and 2020YFE0202200). Clinical Research Plan of SHDC (No. SHDC2020CR5007). Shanghai Municipal Key Clinical Specialty, CAMS Innovation Fund for Medical Sciences (CIFMS) (2019-I2M-5-058).

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Author notes

  1. These authors contributed equally: Jun Gao, Yuan Fang, Jiafeng Chen, Zheng Tang.

Authors and Affiliations

  1. Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China

    Jun Gao, Yuan Fang, Jiafeng Chen, Zheng Tang, Mengxin Tian, Xifei Jiang, Chenyang Tao, Run Huang, Guiqi Zhu, Weifeng Qu, Xiaoling Wu, Jian Zhou, Jia Fan, Weiren Liu & Yinghong Shi

  2. Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China

    Jun Gao, Yuan Fang, Jiafeng Chen, Zheng Tang, Xifei Jiang, Chenyang Tao, Guiqi Zhu, Weifeng Qu, Xiaoling Wu, Jian Zhou, Jia Fan, Weiren Liu & Yinghong Shi

  3. Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China

    Jun Gao, Yuan Fang, Jiafeng Chen, Zheng Tang, Mengxin Tian, Xifei Jiang, Chenyang Tao, Run Huang, Guiqi Zhu, Weifeng Qu, Xiaoling Wu, Jian Zhou, Jia Fan, Weiren Liu & Yinghong Shi

  4. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China

    Mengxin Tian & Run Huang

  5. Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    Jian Zhou & Jia Fan

  6. Shanghai Key Laboratory of Organ Transplantation, Shanghai, China

    Jian Zhou, Jia Fan & Yinghong Shi

  7. State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China

    Jian Zhou & Jia Fan

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  1. Jun Gao
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Contributions

JG, YF, J-FC, and ZT performed the experiments; M-XT, X-FJ, C-YT, RH, and G-QZ analyzed the data; JG, W-FQ, and X-LW wrote the paper; JZ, JF, and W-RL supplied the patient samples; JZ, JF, W-RL, and Y-HS conceived this work. All authors approved the final paper.

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Correspondence to Weiren Liu or Yinghong Shi.

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The study protocol was approved by the Research Ethics Committee of Zhongshan Hospital of Fudan University (Shanghai, China), and written informed consent was obtained from each patient.

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Gao, J., Fang, Y., Chen, J. et al. Methyltransferase like 3 inhibition limits intrahepatic cholangiocarcinoma metabolic reprogramming and potentiates the efficacy of chemotherapy. Oncogene 42, 2507–2520 (2023). https://doi.org/10.1038/s41388-023-02760-0

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