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Aberrant promoter hypermethylation inhibits RGMA expression and contributes to tumor progression in breast cancer

Abstract

Breast cancer (BC) is the most common cancer in women worldwide, and the exploration of aberrantly expressed genes might clarify tumorigenesis and help uncover new therapeutic strategies for BC. Although RGMA was recently recognized as a tumor suppressor gene, its detailed biological function and regulation in BC remain unclear. Herein, we found that RGMA was downregulated in BC tissues compared with non-tumorous breast tissues, particularly in metastatic BC samples, and that patients with low RGMA expression manifested a poorer prognosis. Furthermore, DNMT1 and DNMT3A were found to be recruited to the RGMA promoter and induced aberrant hypermethylation, resulting in downregulation of RGMA expression in BC. In contrast, RGMA overexpression suppressed BC cell proliferation and colony-formation capabilities and increased BC cell apoptosis. Furthermore, RGMA knockdown accelerated BC cell proliferation and suppressed cellular apoptosis in vitro and in vivo. Reversal of RGMA promoter methylation with 5-Aza-CdR restored RGMA expression and blocked tumor growth. Overall, DNMT1- and DNMT3A-mediated RGMA promoter hypermethylation led to downregulation of RGMA expression, and low RGMA expression contributed to BC growth via activation of the FAK/Src/PI3K/AKT-signaling pathway. Our data thus suggested that RGMA might be a promising therapeutic target in BC.

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Fig. 1: RGMA was downregulated in BC.
Fig. 2: DNMT1 and DNMT3A-mediated RGMA promoter hypermethylation led to the RGMA downregulation in BC.
Fig. 3: RGMA overexpression inhibited BC cells proliferation and induced cell apoptosis.
Fig. 4: RGMA knockdown promoted BC cells proliferation and suppressed cell apoptosis.
Fig. 5: Low expression of RGMA could accelerate tumor growth, while 5-Aza-CdR treatment could effectively inhibit tumor growth.
Fig. 6: RGMA exerted function in BC cells via FAK/Src/PI3K/AKT signaling pathway.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this paper. This study was supported by the National Natural Science Foundation of China (Grant No. 81872362 and 82072665) and the Taishan Scholars Program of Shandong Province (Grant No. ts201511096).

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PG, YXZ and YL conceived the study; YL, HTL, XC, YWW, YRT, RRM and LS performed the experiments; YL analyzed the data and wrote the paper; YL, HTL and PG revised the paper. All authors have read and approved the final paper.

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Correspondence to Yong-Xin Zou or Peng Gao.

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The authors declare no competing interests.

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This study was approved by the Ethical Committee on Scientific Research of Shandong University.

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Li, Y., Liu, HT., Chen, X. et al. Aberrant promoter hypermethylation inhibits RGMA expression and contributes to tumor progression in breast cancer. Oncogene (2021). https://doi.org/10.1038/s41388-021-02083-y

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