Super-enhancer-associated circPVT1 promotes malignancy of hepatocellular carcinoma via YBX1-mediated RRM2 activation

Abstract

Circular RNAs (circRNAs), the essential members of epigenetic reprogramming, are emerging as an appealing layer in hepatocellular carcinoma (HCC). Super-enhancers (SEs) are large clusters of transcriptional enhancers with the tremendous gene activation potential and are extensively investigated in cancer research. The present study explores and uncovers an SE-related circRNA circPVT1, identifying its biological functions and downstream mechanisms in HCC. CircPVT1 is upregulated in HCC, serving as an independent prognostic factor for patients with HCC. Enrichment of H3K27ac and H3K4me1 modifications has been confirmed at the genomic loci of circPVT1's host gene, and the expression of circPVT1 is triggered by SEs. Functionally, circPVT1 enhances cell propagation and mobility capabilities in vitro, and facilitates tumour growth and metastasis in vivo. Mechanistically, circPVT1 recruits YBX1 into the cell nucleus, promoting the transcription of RRM2. Dysregulation of the circPVT1-RRM2 axis advances HCC malignancy, while inhibition of RRM2 or SE alleviates the effects of circPVT1 overexpression. In conclusion, our work demonstrates that circPVT1 is driven by super-enhancers. CircPVT1 promotes HCC progression via YBX1-mediated transcriptional activation of RRM2. These findings provide constructive insights into exploring the pathogenesis of HCC.