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m6A-modified circABCC4 promotes stemness and metastasis of prostate cancer by recruiting IGF2BP2 to increase stability of CCAR1

Cancer Gene Therapy volume 30, pages 1426–1440 (2023)Cite this article

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Abstract

Prostate cancer (PCa) is a malignant tumor of the urinary system. CircABCC4 has been demonstrated to promote the development of PCa; however, its regulatory mechanisms in PCa progression remain largely unknown. We found that circABCC4 was highly expressed in PCa tissues and cells, and elevated circABCC4 level indicated a poor overall survival of PCa patients. METTL3 overexpression increased circABCC4 expression via m6A modification in PCa cells. Functionally, knockdown of circABCC4 or METTL3 repressed PCa cell stemness, migration, and invasion in vitro and delayed PCa cancer growth and metastasis in vivo. circABCC4 knockdown-mediated inhibition in PCa cell stemness and metastasis could be counteracted by overexpression of wild-type circABCC4 with m6A sites. Mechanistically, circABCC4 recruited IGF2BP2 protein to CCAR1 mRNA, thereby enhancing CCAR1 mRNA stability and subsequent activation of the Wnt/β-catenin pathway. Overexpression of CCAR1 counteracted the inhibitory effect of circABCC4 silencing on PCa cell stemness and metastasis. These results revealed that m6A-modified circABCC4 by METTL3 facilitated PCa cell stemness and metastasis by interacting with IGF2BP2 to increase the stability and expression of CCAR and subsequent expression of Wnt/β-catenin target genes. Our findings suggest circABCC4 as a promising therapeutic target for PCa.

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Fig. 1: circABCC4 and its m6A modification levels are upregulated in PCa and associated with a poor prognosis.
Fig. 2: circABCC4 expression can be enhanced by METTL3-mediated m6A modification.
Fig. 3: METTL3 silencing restrains PCa cell stemness and metastasis via downregulation of circABCC4.
Fig. 4: METTL3 or circABCC4 knockdown represses CCAR1 expression and reduces the levels of Wnt/β-catenin target genes.
Fig. 5: The stability and expression of CCAR1 was enhanced by circABCC4 via direct interaction with IGF2BP2.
Fig. 6: CCAR1 abolishes the inhibitory effect of shcircABCC4 on stemness and metastasis of PCa cells.
Fig. 7: PCa cell growth and metastasis are restrained by METTL3 or circABCC4 depletion in nude mice.
Fig. 8: Knockdown of METTL3 or circABCC4 results in inhibition in expression of CCAR1 and target genes of Wnt/β-catenin pathway in vivo.

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All data generated or analyzed during this study are included in this published article.

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Acknowledgements

We would like to give our sincere gratitude to the reviewers for their constructive comments.

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Authors and Affiliations

  1. Department of Urology, The Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan Province, P.R. China

    Changkun Huang, Ran Xu, Xuan Zhu & Hongyi Jiang

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  1. Changkun Huang
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Contributions

CH: conceptualization, methodology, supervision, writing—original draft preparation, investigation, validation, visualization. RX: data curation, software. XZ: conceptualization, supervision, writing—original draft preparation, writing—reviewing and editing. HJ: conceptualization, supervision, writing—original draft preparation, writing—reviewing and editing.

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Correspondence to Xuan Zhu or Hongyi Jiang.

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The authors declare no competing interests.

Ethics approval and consent to participate

Fifty-six pairs of fresh PCa tissues and paracancerous non-tumor tissues were collected from PCa patients without chemotherapy or radiotherapy before surgery at the Second Xiangya Hospital of Central South University. Informed consent was provided by all participants. Our study was approved by the Research Ethics Committee of the Second Xiangya Hospital of Central South University (No. 2022JJ40719). The animal experiment was approved by the Ethics Committee of the Second Xiangya Hospital of Central South University (No: 2022735).

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Huang, C., Xu, R., Zhu, X. et al. m6A-modified circABCC4 promotes stemness and metastasis of prostate cancer by recruiting IGF2BP2 to increase stability of CCAR1. Cancer Gene Ther 30, 1426–1440 (2023). https://doi.org/10.1038/s41417-023-00650-x

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