BRD4 inhibition sensitizes glioblastoma to radiotherapy by suppressing super-enhancer-driven COL1A1.

Radiotherapy (RT) combined with chemotherapy is the standard treatment for newly diagnosed glioblastoma (GBM). However, the limited RT efficacy and RT-related cancer resistance have spurred interest in radiosensitizing strategies for GBM. We aimed to explore the synergistic efficacy of the bromodomain-containing protein 4 (BRD4) inhibitor I-BET151 in combination with RT for GBM therapy. We found that BRD4 upregulation after RT was correlated with GBM radiosensitivity. I-BET151 sensitized GBM cells to RT by inhibiting cell proliferation and inducing cell apoptosis, thus prolonging survival in subcutaneous and orthotopic murine GL261 GBM mouse models. In vitro, I-BET151 sensitized GBM cells to RT by suppressing proliferation, inducing apoptosis, and increasing sustainable DNA damage. Mechanistically, integrated H3K27ac ChIP-sequencing and RNA-sequencing analysis identified type I collagen (COL1A1) as a key BRD4-dependent super-enhancer (SE)-driven target post-RT, which was also validated by ChIP‒qPCR. Moreover, RNA interference-mediated COL1A1 silencing reduced proliferation, increased apoptosis, and enhanced RT-induced DNA damage, underscoring its pivotal role in BRD4-mediated radioresistance. In conclusion, BRD4 contributes to extracellular matrix remodeling and radioresistance in a SE-driven COL1A1-dependent manner. Thus, targeting BRD4 is a rational strategy to augment the efficacy of RT for GBM treatment.