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LNC942 promoting METTL14-mediated m6A methylation in breast cancer cell proliferation and progression

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Abstract

Increasing evidence supports that long noncoding RNAs (lncRNAs) act as master regulators involved in tumorigenesis and development at the N6-methyladenine (m6A) epigenetic modification level. However, the underlying regulatory mechanism in breast cancer (BRCA) remains elusive. Here, we unveil that LINC00942 (LNC942) exerts its functions as an oncogene in promoting METTL14-mediated m6A methylation and regulating the expression and stability of its target genes CXCR4 and CYP1B1 in BRCA initiation and progression. Specifically, LNC942 and METTL14 were significantly upregulated accompanied with the upregulation of m6A levels in BRCA cells and our included BRCA cohorts (n = 150). Functionally, LNC942 elicits potent oncogenic effects on promoting cell proliferation and colony formation and inhibiting cell apoptosis, subsequently elevating METTL14-mediated m6A methylation levels and its associated mRNA stability and protein expression of CXCR4 and CYP1B1 in BRCA cells. Mechanistically, LNC942 directly recruits METTL14 protein by harboring the specific recognize sequence (+176–+265), thereby stabilized the expression of downstream targets of LNC942 including CXCR4 and CYP1B1 through posttranscriptional m6A methylation modification in vitro and in vivo. Therefore, our results uncover a novel LNC942-METTL14-CXCR4/CYP1B1 signaling axis, which provides new targets and crosstalk m6A epigenetic modification mechanism for BRCA prevention and treatment.

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Fig. 1: The association of LNC942, m6A, and METTL14 expression in BRCA cells and tissues.
Fig. 2: Knockdown LNC942 inhibits m6A and METTL14 expression levels.
Fig. 3: Effects of LNC942 on cell proliferation, colony formation, metastasis, and apoptosis in BRCA cells.
Fig. 4: METTL14 rescued the BRCA cells proliferation inhibition caused by LNC942 knockdown.
Fig. 5: Knockdown LNC942 inhibits RNA stability and expression of CXCR4 and CYP1B1.
Fig. 6: METTL14 rescued the CXCR4, CYP1B1 and m6A expression inhibition caused by LNC942 knockdown.
Fig. 7: METTL14 promoting cell proliferation regulated by LNC942 in vivo.
Fig. 8: Proposed model depicting regulation and roles of LNC942-METTL14- CXCR4/CYP1B1 signaling axis in BRCA cells.

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Data availability

The authors declare that all the data supporting the findings in this study are available in this study and its Supplementary materials, or are available from the corresponding author through reasonable request.

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Acknowledgements

We gratefully appreciate the efforts and contributions of doctors, nurses, and technical staff at the First Hospital of China Medical University, Cancer Hospital of China Medical University.

Funding

This work was supported by grants from the National Natural Science Foundation of China [No. 31828005, 81872905, and 81673475], National Natural Science Foundation of China and Liaoning joint fund key program [No. U1608281], Liaoning Revitalization Talents Program [XLYC1807155], China Postdoctoral Science Foundation (Grant No. 2019M661180), Special Foundation of China postdoctoral science foundation (Grant No. 2019T120225), and Shenyang S&T Projects (19-109-4-09).

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, PR China

    Tong Sun, Zhikun Wu, ** Xu, Yutong Wu, Qiuchen Chen, ** Xu, Yutong Wu, Qiuchen Chen, ** Xu, Yutong Wu, Qiuchen Chen, ** Xu, Yutong Wu, Qiuchen Chen, **angyu Ding, Hao Guo, Boshi Fu, Weifan Yao, Minjie Wei & Huizhe Wu

  2. Department of Anorectal Surgery, First Hospital of China Medical University, Shenyang, 110001, PR China

    Yalun Li

  3. Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, PR China

    Yuanhe Wang

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Contributions

HW, MW, and TS conceived and designed the project. TS, ZW, XW, XD, HG, and WY performed experiments and/or data acquisition and analyses; YW, XH, WQ, SL, DX, YW, QC, YL, YW, and BF contributed technical/reagents materials, analytic tools and/or grant support; HW, MW, and TS prepared, wrote, and/or revision the paper. All authors discussed the results and commented on the paper.

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Correspondence to Minjie Wei or Huizhe Wu.

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This study was approved by the Ethics Committee of China Medical University. All the animal experiments performed in this study were approved by the Institutional Animal Care and Use Committee of China Medical University.

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Sun, T., Wu, Z., Wang, X. et al. LNC942 promoting METTL14-mediated m6A methylation in breast cancer cell proliferation and progression. Oncogene 39, 5358–5372 (2020). https://doi.org/10.1038/s41388-020-1338-9

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