2. Academic Validation
  3. Activation of YAP1 by N6-Methyladenosine-Modified circCPSF6 Drives Malignancy in Hepatocellular Carcinoma

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

  • Cancer Res. 2022 Feb 15;82(4):599-614. doi: 10.1158/0008-5472.CAN-21-1628.
Yunhao Chen  # 1 2 3 4,  Zhenan Ling  # 2 3 4,  Xianlei Cai  # 1 3 4 5,  Yongfang Xu 6,  Zhen Lv 1 3 4,  Da Man 2 3 4,  Jiangzhen Ge 2 3 4,  Chengkuan Yu 2 3 4,  Deguo Zhang 2 3 4,  Yanpeng Zhang 7,  Haiyang Xie 1 2 3 4,  Lin Zhou 1 2 3 4,  Jian Wu 1 2 3 4,  Shusen Zheng 1 2 3 4
Affiliations

Affiliations

  • 1 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, Hangzhou, P.R. China.
  • 2 NHC Key Laboratory of Combined Multi-organ Transplantation, Zhejiang Province, Hangzhou, P.R. China.
  • 3 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), Zhejiang Province, Hangzhou, P.R. China.
  • 4 Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou, P.R. China.
  • 5 Department of General Surgery, Ningbo Medical Center Lihuili Hospital, Zhejiang Province, Ningbo, P.R. China.
  • 6 Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
  • 7 Department of Thoracic Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi Province, P.R. China.
  • # Contributed equally.
PMID: 34916222 DOI: 10.1158/0008-5472.CAN-21-1628
Abstract

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.

Figures
Products