BET domain functions in IDH1 R132H /p53 mut /ATRX loss astrocytoma malignancy

Grade II/III astrocytomas are the most common primary brain cancer in young adults and are increasingly recognized as epigenetically driven tumors. Their defining mutational background IDH1 R132H ,p53 mut , and ATRX loss (triple-mut) establishes a hypermethylated and chromatin-disrupted state that reshapes transcriptional networks and creates unique therapeutic vulnerabilities distinct from primary glioblastoma (GBM). This epigenetically altered landscape suggests that tumor progression and treatment response in triple-mut astrocytoma are strongly influenced by chromatin-based mechanisms that can be targeted pharmacologically. BET proteins as epigenetic readers that regulate gene transcription by binding acetylated histone and recruiting master transcription factors to chromatin, yet the specific roles of individual BET family members and their bromodomains remain poorly understood. Analysis of TCGA datasets revealed that BRD3 and BRD2 expressions are significantly elevated in clinical triple-mut gliomas compared to IDH1 wild-type gliomas. Consistently, the immunoblot analysis showed that BRD3 expression is induced by the triple-mut and further enhanced by ionizing radiation (IR) and temozolomide (TMZ) treatment . Functionally, inhibition of BET proteins using either pan-BET inhibitors (JQ1, OTX015) or bromodomain 1 (BD1)-selective inhibitor GSK778-but not bromodomain 2 (BD2)-selective inhibitor GSK620- markedly reduces triple-mut glioma cell growth and impairs neurosphere self-renewal , and enhances TMZ-induced cell death . Moreover, BD1 inhibition significantly suppresses PD-L1 induction triggered by the triple-mut, IR/TMZ treatment, or IFN-gamma stimulation. Mechanistically, we find that BD1 inhibition decreases YAP1 and TAZ expression and disrupts YAP1/TAZ transcriptional signaling, whereas BD2 inhibition does not. These findings identify a BD1-dependent transcriptional network that regulates astrocytoma cell phenotype and contributes to an immunosuppressive microenvironment. Targeting BD1 represents a rational therapeutic strategy by simultaneously suppressing tumor cell-intrinsic oncogenic signaling (e.g.,YAP1/TAZ signaling) and reshaping the immunosuppressive microenvironment.