Journal Article

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

Zhang, Liwei, Li, Haocheng, Xi, Qiaoran, Xie, Luyang, Yang, Shuangrui, Zhou, Wei, Li, Xiaohan, Qiao, Huimin, Mi, Da, Xu, Cheng, Pan, Changcun, Jiang, Zhuang, Tang, Yujie

2025

Overview

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. Diffuse intrinsic pontine glioma (DIPG) is driven by H3K27M oncohistones, but the exact related mechanisms are poorly understood. Here, the authors identify an H3.3K27M oncohistone-driven CREB5/ID1 axis that promotes transcriptional changes and progression in DIPG, which could represent a potential therapeutic target.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14 / 14/19 / 45/15 / 45/29 / 45/77 / 45/88 / 45/90 / 45/91 / 59 / 59/5 / 631/337/176 / 631/67/1059 / 631/67/1922 / 631/67/68/2486 / 631/67/69 / 96 / 96/106 / 96/109 / 96/95 / Animals / Brain Stem Neoplasms - genetics / Brain Stem Neoplasms - metabolism / Brain Stem Neoplasms - pathology / BRG1 protein / Cell Line, Tumor / Chromatin remodeling / Combined treatment / Cyclic AMP Response Element-Binding Protein - genetics / Cyclic AMP Response Element-Binding Protein - metabolism / Diffuse Intrinsic Pontine Glioma - genetics / Diffuse Intrinsic Pontine Glioma - metabolism / Diffuse Intrinsic Pontine Glioma - pathology / DNA Helicases - genetics / DNA Helicases - metabolism / Enhancers / Epigenesis, Genetic / Epigenetics / Gene Expression Regulation, Neoplastic / Glioma / Glioma - genetics / Glioma - metabolism / Glioma - pathology / Histones - genetics / Histones - metabolism / Humanities and Social Sciences / Humans / Id1 protein / Inhibitor of Differentiation Protein 1 / Malignancy / Mice / multidisciplinary / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Pediatrics / Science / Science (multidisciplinary) / Signal Transduction / Therapeutic targets / Transcription Factors - genetics / Transcription Factors - metabolism / Tumors