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Updated: Aug 16, 2025

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BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network

Xueqin Sun1, Olaf Klingbeil1, Bin Lu1

  • 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.

Nature
|December 21, 2022
PubMed

Insights

A novel epigenetic mechanism in glioblastoma (GBM) involves BRD8 maintaining a repressive chromatin state, hindering p53

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • p53 (TP53) tumor suppressor function is crucial in human cancers.
  • p53 is frequently unmutated in glioblastoma (GBM), the deadliest adult brain cancer.
  • The mechanism countering p53 in wild-type GBM (TP53WT) is largely unknown.

Purpose of the Study:

  • To elucidate the epigenetic mechanisms counteracting p53 in TP53WT GBM.
  • To identify potential therapeutic targets for TP53WT GBM.

Main Methods:

  • Investigated the role of bromodomain-containing protein 8 (BRD8) in GBM.
  • Analyzed chromatin states, H2AZ occupancy, and p53 target gene transactivation.
  • Examined BRD8 and H2AZ expression in patient-derived GBM cells.

Main Results:

  • BRD8, via the EP400 complex, maintains H2AZ at p53 target loci, creating repressive chromatin.
  • This epigenetic state prevents p53 transactivation and promotes GBM cell proliferation.
  • Targeting BRD8's bromodomain displaces H2AZ, enhances chromatin accessibility, and restores p53 activity, inducing cell cycle arrest and tumor suppression.
  • BRD8 and H2AZ are highly expressed in proliferating GBM cells, inversely correlated with p53 target CDKN1A (p21).

Conclusions:

  • BRD8 is a key epigenetic regulator that suppresses p53 function in TP53WT GBM.
  • BRD8 represents a selective epigenetic vulnerability in GBM.
  • Targeting the BRD8 bromodomain offers a potential therapeutic strategy for TP53WT GBM.

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