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

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 circA...

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Bibliographic Details
Published in:Cancer gene therapy 2023-10, Vol.30 (10), p.1426-1440
Main Authors: Huang, Changkun, Xu, Ran, Zhu, Xuan, Jiang, Hongyi
Format: Article
Language:English
Subjects:
631/67/589/466
692/699/67/589/466
Biomedical and Life Sciences
Biomedicine
Cell migration
Gene Expression
Gene Therapy
Metastases
Metastasis
mRNA stability
N6-methyladenosine
Prostate cancer
Therapeutic targets
Wnt protein
β-Catenin
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Summary: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.
ISSN:0929-1903
1476-5500
DOI:10.1038/s41417-023-00650-x