2. Academic Validation
  3. Dual inhibition of FACT and RRM2 suppresses the progression of pancreatic ductal adenocarcinoma driven by the oncohistone H2BG53D

Dual inhibition of FACT and RRM2 suppresses the progression of pancreatic ductal adenocarcinoma driven by the oncohistone H2BG53D

  • Cell Rep. 2025 Nov 23;44(12):116596. doi: 10.1016/j.celrep.2025.116596.
Tiantian Qin 1,  Yi Ching Esther Wan 1,  Shiman Hu 1,  Jiaohua Chen 1,  Xiaoxuan Zhu 1,  Jiaqi Zhou 2,  Yabin Chen 3,  Xin Wang 3,  Zongli Zheng 1,  Landon Long Chan 4,  Hoi Leong Xavier Wong 5,  Haojie Jin 6,  Junhong Han 7,  Qing Li 8,  Haiyun Gan 2,  Kui Ming Chan 9
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, College of Biomedicine, City University of Hong Kong, Hong Kong SAR 999077, China; Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen 518000, China.
  • 2 Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518000, China.
  • 3 Department of Surgery, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
  • 4 Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
  • 5 School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
  • 6 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200000, China.
  • 7 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610000, China.
  • 8 State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100000, China.
  • 9 Department of Biomedical Sciences, College of Biomedicine, City University of Hong Kong, Hong Kong SAR 999077, China; Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen 518000, China. Electronic address: [email protected].
PMID: 41284383 DOI: 10.1016/j.celrep.2025.116596
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal Cancer with frequent genetic mutations. We previously reported the identification of the histone H2BG53D mutation and revealed that this mutation destabilizes nucleosomes and promotes cell migration. However, how H2BG53D impacts chromatin and its significance in PDAC development remain unknown. Using genetically engineered mouse models, we demonstrate that H2BG53D promotes PDAC initiation and metastasis. Moreover, H2BG53D elevates the interaction between nucleosomes and the facilitates chromatin transcription (FACT) complex. FACT depletion reverses transcriptional changes and oncogenic effects induced by H2BG53D. In search of therapeutic strategies, our genome-wide CRISPR-Cas9 screen identified ribonucleotide reductase regulatory subunit M2 (RRM2) as a druggable target for H2BG53D-PDAC. Remarkably, dual inhibition of RRM2 and FACT markedly inhibits PDAC development and significantly prolongs the survival of H2BG53D-PDAC mice. This study deciphers the roles and mechanisms of H2BG53D in PDAC and proposes a promising therapeutic strategy for this aggressive Cancer.

Keywords

CP: cancer; CP: molecular biology; CRISPR-Cas9 screen; FACT; H2BG53D; KPC model; PDAC; PDAC metastasis; PDAC progression; RRM2; oncohistone; therapeutic strategy.

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