Dual inhibition of FACT and RRM2 suppresses the progression of pancreatic ductal adenocarcinoma driven by the oncohistone H2BG53D
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.
Authors
- Hoi Leong Xavier Wong (ORCID: https://orcid.org/0000-0002-2460-4808)
- Haojie Jin (ORCID: https://orcid.org/0000-0001-9295-1951)
- Junhong Han (ORCID: https://orcid.org/0000-0002-3371-8698)
- Kui Ming Chan (ORCID: https://orcid.org/0000-0001-6430-3340)
- Tiantian Qin (ORCID: https://orcid.org/0000-0003-3290-180X)
- Zongli Zheng (ORCID: https://orcid.org/0000-0003-4849-4903)
- Landon L. Chan (ORCID: https://orcid.org/0000-0002-1306-5896)
- Yi Ching Esther Wan (ORCID: https://orcid.org/0000-0002-5916-3336)
- Haiyun Gan (ORCID: https://orcid.org/0000-0002-0293-8778)
- Xiaoxuan Zhu (ORCID: https://orcid.org/0000-0002-1664-8034)
- Jiaqi Zhou (ORCID: https://orcid.org/0000-0002-9285-8914)
- Xin Wang (ORCID: https://orcid.org/0000-0002-5122-2418)
- Qing Li (ORCID: https://orcid.org/0000-0003-0251-9159)
- Jianliang Chen (ORCID: https://orcid.org/0000-0003-3780-3889)
- Yabin Chen (ORCID: https://orcid.org/0000-0001-6914-9266)
- S. Jack Hu (ORCID: https://orcid.org/0000-0001-5440-4180)
Institutions
- Hong Kong Baptist University (HK)
- City University of Hong Kong (HK)
- Chinese University of Hong Kong (HK)
- Peking University (CN)
- Sichuan University (CN)
- City University of Hong Kong, Shenzhen Research Institute (CN)
- Prince of Wales Hospital (CN)
- Synthetic Genomics (United States) (US)
- State Key Laboratory of Oncogene and Related Genes (CN)
- Center for Life Sciences (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-11-23
- DOI
- https://doi.org/10.1016/j.celrep.2025.116596
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.00