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An oncohistone-driven H3.3K27M/CREB5/ID1 axis maintains the stemness and malignancy of diffuse intrinsic pontine glioma

Author

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  • Wei Zhou

    (Tsinghua University)

  • Cheng Xu

    (Capital Medical University)

  • Shuangrui Yang

    (Tsinghua University)

  • Haocheng Li

    (Tsinghua University)

  • Changcun Pan

    (Capital Medical University)

  • Zhuang Jiang

    (Capital Medical University)

  • Luyang Xie

    (Capital Medical University)

  • Xiaohan Li

    (Tsinghua University)

  • Huimin Qiao

    (Tsinghua University)

  • Da Mi

    (Tsinghua University)

  • Yujie Tang

    (Shanghai Jiao Tong University School of Medicine)

  • Liwei Zhang

    (Capital Medical University
    China National Clinical Research Center for Neurological Diseases)

  • Qiaoran Xi

    (Tsinghua University
    Tsinghua University)

Abstract

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.

Suggested Citation

  • Wei Zhou & Cheng Xu & Shuangrui Yang & Haocheng Li & Changcun Pan & Zhuang Jiang & Luyang Xie & Xiaohan Li & Huimin Qiao & Da Mi & Yujie Tang & Liwei Zhang & Qiaoran Xi, 2025. "An oncohistone-driven H3.3K27M/CREB5/ID1 axis maintains the stemness and malignancy of diffuse intrinsic pontine glioma," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58795-2
    DOI: 10.1038/s41467-025-58795-2
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