m6A修饰的circABCC4通过招募IGF2BP2增加CCAR1的稳定性，促进前列腺癌的干细胞特性和转移。
m6A-modified circABCC4 promotes stemness and metastasis of prostate cancer by recruiting IGF2BP2 to increase stability of CCAR1.
发表日期：2023 Aug 10
作者：
Changkun Huang, Ran Xu, Xuan Zhu, Hongyi Jiang
来源：
CANCER GENE THERAPY
摘要：
前列腺癌（PCa）是泌尿系统的恶性肿瘤。已经证明循环ABCC4（circABCC4）促进了PCa的发展，但其在PCa进展中的调控机制仍然大部分未知。我们发现circABCC4在PCa组织和细胞中高度表达，而且高表达的circABCC4水平预示着PCa患者的整体生存不良。METTL3过表达通过m6A修饰增加了PCa细胞中circABCC4的表达。在功能上，抑制circABCC4或METTL3的表达抑制了体外的PCa细胞干性、迁移和侵袭，并延缓了体内PCa癌症的生长和转移。通过具有m6A位点的野生型circABCC4的过表达可以抵消circABCC4的沉默介导的PCa细胞干性和转移抑制作用。在机制上，circABCC4招募了IGF2BP2蛋白到CCAR1 mRNA上，从而增强CCAR1 mRNA的稳定性，并进一步激活了Wnt/β-catenin通路。CCAR1的过表达抵消了circABCC4沉默对PCa细胞干性和转移的抑制作用。这些结果揭示了通过METTL3介导的m6A修饰的circABCC4促进了PCa细胞干性和转移，通过与IGF2BP2相互作用提高了CCAR1的稳定性和表达，并进一步调节了Wnt/β-catenin靶基因的表达。我们的研究结果表明，circABCC4可能是PCa的一个有前景的治疗靶点。© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
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.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.