2. Academic Validation
  3. FBL promotes hepatocellular carcinoma tumorigenesis and progression by recruiting YY1 to enhance CAD gene expression

FBL promotes hepatocellular carcinoma tumorigenesis and progression by recruiting YY1 to enhance CAD gene expression

  • Cell Death Dis. 2025 Apr 27;16(1):348. doi: 10.1038/s41419-025-07684-z.
Yafei Zhi # 1 2 3 4 5 6,  Yan Guo # 1 2,  Shiliang Li # 7,  Xinyu He 1 2,  Huifang Wei 1 2,  Kyle Laster 2,  Qiong Wu 1 2,  Dengyun Zhao 1 2,  Jinxin Xie 8,  Shanshan Ruan 8,  Nicholas R Lemoine 9 10,  Honglin Li 11 12 13,  Zigang Dong 14 15 16 17 18,  Kangdong Liu 19 20 21 22 23 24
Affiliations

Affiliations

  • 1 State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer; The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
  • 2 China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.
  • 3 Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou, China.
  • 4 Innovation Center of Basic Research for Metabolic-Associated Fatty Liver Disease, Ministry of Education of China, Zhengzhou, China.
  • 5 Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, China.
  • 6 Cancer Chemistry International Collaboration Laboratory, Zhengzhou, China.
  • 7 Innovation Center for AI and Drug Discovery, East China Normal University, Shanghai, China.
  • 8 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
  • 9 Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy; The School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. bci-director@qmul.ac.uk.
  • 10 Center for Cancer Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK. bci-director@qmul.ac.uk.
  • 11 Innovation Center for AI and Drug Discovery, East China Normal University, Shanghai, China. hlli@ecust.edu.cn.
  • 12 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China. hlli@ecust.edu.cn.
  • 13 Lingang Laboratory, Shanghai, China. hlli@ecust.edu.cn.
  • 14 State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer; The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China. dongzg@zzu.edu.cn.
  • 15 China-US (Henan) Hormel Cancer Institute, Zhengzhou, China. dongzg@zzu.edu.cn.
  • 16 Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou, China. dongzg@zzu.edu.cn.
  • 17 Innovation Center of Basic Research for Metabolic-Associated Fatty Liver Disease, Ministry of Education of China, Zhengzhou, China. dongzg@zzu.edu.cn.
  • 18 Cancer Chemistry International Collaboration Laboratory, Zhengzhou, China. dongzg@zzu.edu.cn.
  • 19 State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer; The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China. kdliu@zzu.edu.cn.
  • 20 China-US (Henan) Hormel Cancer Institute, Zhengzhou, China. kdliu@zzu.edu.cn.
  • 21 Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou, China. kdliu@zzu.edu.cn.
  • 22 Innovation Center of Basic Research for Metabolic-Associated Fatty Liver Disease, Ministry of Education of China, Zhengzhou, China. kdliu@zzu.edu.cn.
  • 23 Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, China. kdliu@zzu.edu.cn.
  • 24 Cancer Chemistry International Collaboration Laboratory, Zhengzhou, China. kdliu@zzu.edu.cn.
  • # Contributed equally.
PMID: 40289107 DOI: 10.1038/s41419-025-07684-z
Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Accumulating evidence suggests that epigenetic dysregulation contributes to the initiation and progression of HCC. We aimed to investigate key epigenetic regulators that contribute to tumorigenesis and progression, providing a theoretical basis for targeted therapy for HCC. We performed a comprehensive epigenetic analysis of differentially expressed genes in LIHC from the TCGA database. We identified fibrillarin (FBL), an rRNA 2'-O-methyltransferase, as an essential contributor to HCC. A series of in vitro and in vivo biological experiments were performed to investigate the potential mechanisms of FBL. FBL knockdown suppressed the proliferation of HCC cells. In vivo studies using cell-derived xenograft (CDX), patient-derived xenograft (PDX), and diethylnitrosamine (DEN)-induced HCC models in Fbl liver-specific knockout mice demonstrated the critical role of FBL in HCC carcinogenesis and progression. Mechanistically, FBL regulates the expression of CAD in HCC cells by recruiting YY1 to the CAD promoter region. We also revealed that fludarabine phosphate is a novel inhibitor of FBL and can inhibit HCC growth in vitro and in vivo. The antitumor activity of lenvatinib has been shown to be synergistically enhanced by fludarabine phosphate. Our study highlights the cancer-promoting role of the FBL-YY1-CAD axis in HCC and identifies fludarabine phosphate as a novel inhibitor of FBL. A schematic diagram depicting the FBL-YY1-CAD signaling pathway and its regulatory role in HCC progression.

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