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

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-04-17 DOI:10.1038/s41467-025-58795-2

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

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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.

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肿瘤组蛋白驱动的H3.3K27M/CREB5/ID1轴维持弥漫性内生性脑桥胶质瘤的干性和恶性

弥漫性内在脑桥胶质瘤（DIPG）是一种由H3K27M癌组蛋白驱动的致死性儿童癌症，表现出异常的表观遗传调控和干细胞样状态。在这里，我们发现了一个涉及H3.3K27M癌组蛋白CREB5/ID1的轴，它维持了DIPG细胞的干样状态，促进了恶性肿瘤。研究表明，CREB5介导H3.3K27M/ACVR1WT亚型中ID1水平升高，促进肿瘤生长；而BMP信号在H3.1K27M/ACVR1MUT亚型中调控这一过程。此外，我们发现H3.3K27M通过重塑CREB5位点的H3K27me3景观，特别是在超增强子区域，直接增强CREB5的表达。此外，我们阐明了CREB5和BRG1 （SWI/SNF染色质重塑复合体催化亚基）在驱动H3.3K27M DIPG致癌转录变化中的协同作用。有趣的是，用ABBV-075破坏CREB5超增强子可显著降低其表达并抑制H3.3K27M DIPG肿瘤生长。ABBV-075联合BRG1抑制剂治疗H3.3K27M DIPG是一种很有前景的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.