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METTL3 potentiates progression of cervical cancer by suppressing ER stress via regulating m6A modification of TXNDC5 mRNA

Abstract

N6-methyladenosine (m6A) is the most abundant chemical modification on mRNA and plays significant roles in many bioprocesses. However, the functions of m6A on cervical cancer (CC) tumorigenesis remain unclear. Here we found methyltransferase-like 3 (METTL3), a core member of the m6A methyltransferase family, was greatly upregulated as an independent prognostic factor in CC. Mechanistically, the transcription factor ETS1 recruited P300 and WDR5 which separately mediated H3K27ac and H3K4me3 histone modification in the promoter of METTL3 and induced METTL3 transcription activation. Furthermore, we identified TXNDC5 as a target of METTL3-mediated m6A modification through MeRIP-seq, and revealed that METTL3-mediated TXNDC5 expression relied on the m6A reader-dependent manner. Functionally, we verified that METTL3 promoted proliferation and metastasis of CC cells by regulating of TXNDC5 expression through in vitro and in vivo experiments. In addition, our study verified the effect of METTL3/TXNDC5 axis on ER stress. Taken together, METTL3 facilitates the malignant progression of CC, suggesting that METTL3 might be a potential prognostic biomarker and therapeutic target for CC.

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Fig. 1: METTL3 expression is upregulated and correlated with prognosis in CC.
Fig. 2: METTL3 promotes proliferation and metastasis of CC cells in vitro and in vivo.
Fig. 3: ETS1 activates METTL3 promoter region via P300 mediated H3K27ac and WDR5 mediated H3K4me3 transcription.
Fig. 4: METTL3-induced m6A modification is responsible for the upregulation of TXNDC5.
Fig. 5: METTL3 promotes TXNDC5 mRNA expression via an m6A-reader-dependent pathway.
Fig. 6: Silenced METTL3 reverses the effects of TXNDC5 on proliferation and metastasis of CC cells.
Fig. 7: METTL3 diminished the CC cell death caused by ER stress through TXNDC5.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No.81872080), Jiangsu Provincial Medical Talent (ZDRCA2016055).

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QYD and FCH performed the experiments and wrote the manuscript. WQD partially participated in vivo experiments. XLS and XJ partially participated in vitro experiments. All authors contributed to data analysis. LSZ reviewed and supervised the manuscript. DSP obtained funding and designed the research. All authors read and approved the final manuscript.

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Correspondence to Lan-Sheng Zhang or Dong-Sheng Pei.

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Du, QY., Huo, FC., Du, WQ. et al. METTL3 potentiates progression of cervical cancer by suppressing ER stress via regulating m6A modification of TXNDC5 mRNA. Oncogene 41, 4420–4432 (2022). https://doi.org/10.1038/s41388-022-02435-2

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