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LncRNA UCA1 promotes SOX12 expression in breast cancer by regulating m6A modification of miR-375 by METTL14 through DNA methylation

Cancer Gene Therapy volume 29, pages 1043–1055 (2022)Cite this article

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Abstract

Breast cancer, a multifactorial disease, represents one of the leading causes of cancer-related morbidity and mortality in women. This study set out to elucidate the underlying mechanism by which lncRNA UCA1 affects the m6A modification of miR-375 by mediating the DNA methylation of METTL14 and then altering SOX12 expression in breast cancer. First, the expression patterns of lncRNA UCA1, miR-375, and apoptosis-related factors were quantitated by means of RT-qPCR and western blot analysis. In addition, the proliferation, invasion, and apoptosis of cells were detected using CCK-8, Transwell, and flow cytometry, respectively. RIP was performed to further uncover the interaction of lncRNA UCA1 and DNA methyltransferases, and MSP was employed for METTL14 promoter region methylation. The DNA methyltransferase enrichment in the METTL14 promoter region was measured by ChIP. The targeting relationship between miR-375 and SOX12 was confirmed by bioinformatics analysis and dual-luciferase report assay. Lastly, the aforementioned mechanism was also verified using tumor xenograft in vivo. It was found the elevated lncRNA UCA1 expression levels serve as a risk factor of poor prognosis in breast cancer. Meanwhile, silencing lncRNA UCA1 could inhibit the proliferation and invasion, but promote apoptosis of breast cancer cells by reducing the DNA methylation of METTL14 and augmenting its expression. Furthermore, METTL14 was observed to mediate the low miR-375 expression through m6A modification, leading to increased SOX12 expression levels in breast cancer. Altogether, findings obtained in our study indicated that silencing lncRNA UCA1 curbed the progression of breast cancer through the METTL14-miR-375-SOX12 axis.

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Fig. 1: LncRNA UCA1 expression is elevated in breast cancer and this elevation indicates poor prognosis of patients.
Fig. 2: LncRNA UCA1 silencing impairs the proliferation and invasion but induces apoptosis of T47D breast cancer cells.
Fig. 3: LncRNA UCA1 inhibits METTL14 expression by DNA methylation in breast cancer.
Fig. 4: Silencing lncRNA UCA1 inhibits the proliferation and invasion but promotes apoptosis of T47D cells by mediating METTL14 expression.
Fig. 5: METTL14 mediates low miR-375 expression via m6A modification in breast cancer cells.
Fig. 6: METTL14 medicates high SOX12 expression via m6A modification of miR-375 in breast cancer.
Fig. 7: Elevated METTL14 inhibits T47D cell proliferation and invasion and promotes apoptosis through the miR-375-SOX12 axis.
Fig. 8: Silencing lncRNA UCA1 weakens T47D cell proliferation and invasion but enhances apoptosis by mediating the METTL14-miR-375-SOX12 axis.
Fig. 9: Silencing lncRNA UCA1 inhibits breast cancer growth in vivo via regulation of the METTL14-miR-375-SOX12 axis.
Fig. 10: Mechanism diagram of lncRNA UCA1 affecting breast cancer progression.

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Acknowledgements

The authors thank the reviewers for their helpful comments.

Funding

This work is supported by the Youth Fund of the First Hospital of Lanzhou University (ldyyyn2019-85).

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Authors and Affiliations

  1. Department of Internal Medicine-Oncology, The First Hospital of Lanzhou University, 730000, Lanzhou, P.R. China

    Chengpeng Zhao & Xiaoling Ling

  2. The First School of Clinical Medicine, Lanzhou University, 730000, Lanzhou, P.R. China

    Yunxia Xia & Bingxue Yan

  3. Department of Oncology Surgery, The First Hospital of Lanzhou University, 730000, Lanzhou, P.R. China

    Quanlin Guan

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  1. Chengpeng Zhao
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Contributions

CPZ designed the study. XLL, YXX, and BXY collated the data, carried out data analyses, and produced the initial draft of the manuscript. QLG contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Quanlin Guan.

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Zhao, C., Ling, X., Xia, Y. et al. LncRNA UCA1 promotes SOX12 expression in breast cancer by regulating m6A modification of miR-375 by METTL14 through DNA methylation. Cancer Gene Ther 29, 1043–1055 (2022). https://doi.org/10.1038/s41417-021-00390-w

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