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 (nā=ā150). 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 (+176ā+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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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.
Change history
15 February 2022
A Correction to this paper has been published: https://doi.org/10.1038/s41388-022-02194-0
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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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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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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, 5358ā5372 (2020). https://doi.org/10.1038/s41388-020-1338-9
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DOI: https://doi.org/10.1038/s41388-020-1338-9
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