Dual inhibition of FACT and RRM2 suppresses the progression of pancreatic ductal adenocarcinoma driven by the oncohistone H2BG53D
Year: 2025
Type: article
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.
Source: Cell Reports
Authors: Tiantian Qin, Yi Ching Esther Wan, Shiman Hu, Jiaohua Chen, Xiaoxuan Zhu, Jiaqi Zhou, Yabin Chen, Xin Wang, Zongli Zheng, Landon Long Chan, Hoi Leong Xavier Wong, Haojie Jin, Junhong Han, Qing Li, Haiyun Gan, Kui Ming Chan
Institutions: City University of Hong Kong, City University of Hong Kong, Shenzhen Research Institute, Chinese Academy of Sciences, Shenzhen Institutes of Advanced Technology, Shenzhen Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Baptist University, Shanghai Jiao Tong University, Renji Hospital, Shanghai Cancer Institute, State Key Laboratory of Oncogene and Related Genes, Sichuan University, West China Medical Center of Sichuan University, West China Hospital of Sichuan University, State Key Laboratory of Biotherapy, Peking University, Center for Life Sciences, State Key Laboratory of Protein and Plant Gene Research
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: G4359067139, G5101794735, G7833763351
OpenAlex ID: W4416551436