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METTL3 stabilization by PIN1 promotes breast tumorigenesis via enhanced m6A-dependent translation

Oncogene volume 42, pages 1010–1023 (2023)Cite this article

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Abstract

Methyltransferase-like 3 (METTL3) is the catalytic subunit of the N6-adenosine methyltransferase complex responsible for N6-methyladenosine (m6A) modification of mRNA in mammalian cells. Although METTL3 expression is increased in several cancers, the regulatory mechanisms are unclear. We explored the regulatory roles of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in METTL3 stability and m6A modification of mRNA. PIN1 interacted with METTL3 and prevented its ubiquitin-dependent proteasomal and lysosomal degradation. It stabilized METTL3, which increased the m6A modification of transcriptional coactivator with PDZ-binding motif (TAZ) and epidermal growth factor receptor (EGFR) mRNA, resulting in their efficient translation. PIN1 knockout altered the distribution of TAZ and EGFR mRNA from polysomes into monosomes. Inhibition of MEK1/2 kinases and PIN1 destabilized METTL3, which impeded breast cancer cell proliferation and induced cell cycle arrest at the G0/G1 phases. METTL3 knockout reduced PIN1 overexpression-induced colony formation in MCF7 cells and enhanced tumor growth in 4T1 cells in an orthotopic mouse model. In clinical settings, METTL3 expression significantly increased with tumor progression and was positively correlated with PIN1 expression in breast cancer tissues. Thus, PIN1 plays a regulatory role in mRNA translation, and the PIN1/METTL3 axis may be an alternative therapeutic target in breast cancer.

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Fig. 1: PIN1 expression is elevated and positively correlated with METTL3 abundance in human breast cancer.
Fig. 2: PIN1 interacted with METTL3 via its PPIase domain in a phosphorylation-dependent manner.
Fig. 3: PIN1 enhanced METTL3 stability by reducing its ubiquitination and lysosomal degradation.
Fig. 4: PIN1 promoted the m6A modification of TAZ and EGFR.
Fig. 5: PIN1 promoted the m6A-dependent translation of TAZ and EGFR via increased polysome assembly.
Fig. 6: Combinatorial treatment with MEKi and ATRA reduced the m6A-dependent translation of TAZ and EGFR.
Fig. 7: Mettl3 knockout suppressed PIN1-induced breast tumorigenesis in vivo.

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Data availability

The proteomic analysis results published here are wholly- or partly based upon the data generated through The Cancer Dependency Map (DepMap) Project at the Broad Institute (The Cancer Target Discovery and Development screening project) and TCGA. The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) funded by the Korean government (MSIP; NRF-2019R1A2C2002113, NRF-2022R1A2C2005094) and the Ministry of Science, Information and Communications Technology (ICT), and Future Planning (NRF-2022R1A5A2030454).

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Authors and Affiliations

  1. College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea

    Poshan Yugal Bhattarai, Garam Kim & Hong Seok Choi

  2. Department of Pathology, School of Medicine, Chosun University, Gwangju, 61452, Republic of Korea

    Sung-Chul Lim

  3. Department of Cellular and Molecular Medicine, College of Medicine, Chosun University, Gwangju, 61452, Republic of Korea

    Ramesh Mariappan & Takbum Ohn

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Contributions

Conceptualization, PYB and HSC; methodology, PYB and GK; software, PYB and GK; validation and investigation, PYB, GK, RM and TO; resources, HSC; writing-original draft preparation, PYB; writing-review and editing, HSC; visualization, SCL; supervision, HSC; project administration, HSC; funding acquisition, HSC. All authors have read and agree to the published version of the manuscript.

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Correspondence to Hong Seok Choi.

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Bhattarai, P.Y., Kim, G., Lim, SC. et al. METTL3 stabilization by PIN1 promotes breast tumorigenesis via enhanced m6A-dependent translation. Oncogene 42, 1010–1023 (2023). https://doi.org/10.1038/s41388-023-02617-6

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