Chen Yunhao, Du Chengli, Tang Jie, Zhao Yanchun, Xie Haiyang, Zheng Shusen, Tu Zhengliang
Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang Province, China; Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China.
Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China.
Cancer Lett. 2024 Dec 16;611:217395. doi: 10.1016/j.canlet.2024.217395.
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.
环状RNA（circRNAs）作为表观遗传重编程的重要成员，正成为肝细胞癌（HCC）中一个引人关注的层面。超级增强子（SEs）是具有巨大基因激活潜力的转录增强子大簇，在癌症研究中受到广泛研究。本研究探索并揭示了一种与SE相关的环状RNA circPVT1，确定了其在HCC中的生物学功能和下游机制。CircPVT1在HCC中上调，是HCC患者的独立预后因素。在circPVT1宿主基因的基因组位点已证实H3K27ac和H3K4me1修饰富集，且circPVT1的表达由SEs触发。在功能上，circPVT1在体外增强细胞增殖和迁移能力，在体内促进肿瘤生长和转移。机制上，circPVT1将YBX1招募到细胞核中，促进RRM2的转录。circPVT1-RRM2轴的失调促进了HCC的恶性发展，而抑制RRM2或SE可减轻circPVT1过表达的影响。总之，我们的工作表明circPVT1由超级增强子驱动。CircPVT1通过YBX1介导的RRM2转录激活促进HCC进展。这些发现为探索HCC的发病机制提供了建设性的见解。
