An oncohistone-driven H3.3K27M/CREB5/ID1 axis maintains the stemness and malignancy of diffuse intrinsic pontine glioma
Diffuse intrinsic pontine glioma (DIPG), a lethal pediatric cancer driven by H3K27M oncohistones, exhibits aberrant epigenetic regulation and stem-like cell states. Here, we uncover an axis involving H3.3K27M oncohistones, CREB5/ID1, which sustains the stem-like state of DIPG cells, promoting malignancy. We demonstrate that CREB5 mediates elevated ID1 levels in the H3.3K27M/ACVR1WT subtype, promoting tumor growth; while BMP signaling regulates this process in the H3.1K27M/ACVR1MUT subtype. Furthermore, we reveal that H3.3K27M directly enhances CREB5 expression by reshaping the H3K27me3 landscape at the CREB5 locus, particularly at super-enhancer regions. Additionally, we elucidate the collaboration between CREB5 and BRG1, the SWI/SNF chromatin remodeling complex catalytic subunit, in driving oncogenic transcriptional changes in H3.3K27M DIPG. Intriguingly, disrupting CREB5 super-enhancers with ABBV-075 significantly reduces its expression and inhibits H3.3K27M DIPG tumor growth. Combined treatment with ABBV-075 and a BRG1 inhibitor presents a promising therapeutic strategy for clinical translation in H3.3K27M DIPG treatment.
Authors
- Da Mi (ORCID: https://orcid.org/0000-0002-7829-1923)
- Haocheng Li (ORCID: https://orcid.org/0009-0001-9237-7520)
- Qiaoran Xi (ORCID: https://orcid.org/0000-0002-7496-4131)
- Zhuang Jiang
- Huimin Qiao (ORCID: https://orcid.org/0000-0001-9556-7832)
- L Z Xie (ORCID: https://orcid.org/0009-0009-9980-9662)
- Yujie Tang (ORCID: https://orcid.org/0000-0001-7647-5780)
- Cheng Xu (ORCID: https://orcid.org/0000-0002-2504-1883)
- Changcun Pan (ORCID: https://orcid.org/0000-0002-7183-9220)
- Wei Zhou (ORCID: https://orcid.org/0009-0009-3676-0793)
- Liwei Zhang (ORCID: https://orcid.org/0000-0003-1919-3765)
- Xiaohan Li (ORCID: https://orcid.org/0009-0003-7761-8570)
- Shuangrui Yang
Institutions
- Shanghai Jiao Tong University (CN)
- Capital Medical University (CN)
- Beijing Tian Tan Hospital (CN)
- National Clinical Research Center for Digestive Diseases (CN)
- Center for Life Sciences (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1038/s41467-025-58795-2
- Citations
- 5
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Memorial Sloan-Kettering Cancer Center
- Westlake University
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Tsinghua University
- Université de Genève
- Université Paris-Saclay
- Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support
- Beijing Municipal Administration of Hospitals
- State Key Laboratory of Membrane Biology