Activation of YAP1 by N6-Methyladenosine–Modified circCPSF6 Drives Malignancy in Hepatocellular Carcinoma

Dec 17, 2021Cancer research

Activation of YAP1 by a Modified Circular RNA Promotes Liver Cancer Growth

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Abstract

Elevated expression of circCPSF6 serves as an independent prognostic factor for worse survival in patients with hepatocellular carcinoma (HCC).

CircCPSF6 is identified as a novel m6A-modified circRNA in HCC.
Demethylation of circCPSF6 is primarily mediated by ALKBH5, leading to its destabilization by YTHDF2.
Loss-of-function experiments show that circCPSF6 supports cell proliferation, motility, and tumor metastasis.
CircCPSF6 activates the expression of YAP1, which is involved in promoting HCC malignancy.
CircCPSF6 competes with PCBP2 for binding to YAP1 mRNA, enhancing YAP1 stability.
Inhibition of YAP1 reverses the effects of circCPSF6 in both laboratory and animal studies.

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UNLABELLED: Circular RNAs (circRNA) and N6-methyladenosine (m6A) modification are extensively involved in the progression of diverse tumors, including hepatocellular carcinoma (HCC). However, the cross-talk between circRNAs and m6A remains elusive in the pathogenesis of HCC. Here we investigated m6A-mediated regulation of circRNAs in HCC. m6A-related circRNAs were identified by integrating information from two published studies, revealing circular cleavage and polyadenylation specific factor 6 (circCPSF6) as a novel m6A-modified circRNA. circCPSF6 was dominated by ALKBH5-mediated demethylation, followed by the recognization and destabilization by YTHDF2. Meanwhile, circCPSF6 was upregulated in HCC specimens, and elevated circCPSF6 expression served as an independent prognostic factor for worse survival of patients with HCC. Loss-of-function assays demonstrated that circCPSF6 maintained cell proliferation and tumorigenicity and reinforced cell motility and tumor metastasis. circCPSF6 triggered expression of YAP1, further activating its downstream cascade. Mechanistically, circCPSF6 competitively bound PCBP2, blunting its binding to YAP1 mRNA, thereby sustaining the stability of YAP1. Functionally, removal of YAP1 reversed the effects of circCPSF6 in vitro and in vivo. Aberrant activation of the circCPSF6-YAP1 axis promoted HCC malignancy. These findings offer novel insights into the regulation of circRNAs by m6A modifications and the role of this epigenetic reprogramming in HCC.

SIGNIFICANCE: This study advances the understanding of the interplay between m6A methylation and circRNAs in hepatocellular carcinoma, highlighting the potential of circCPSF6 as a therapeutic target.

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Activation of YAP1 by N6-Methyladenosine–Modified circCPSF6 Drives Malignancy in Hepatocellular Carcinoma

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