P300-mediated H3K27 acetylation activates the TRAF3IP3/ERK axis to promote glioblastoma progression

Aberrant ERK/MAPK signaling is a hallmark of glioblastoma (GBM) progression, yet the upstream epigenetic and molecular mechanisms sustaining this pathway remain incompletely understood. Here, we identify an SP1/P300/TRAF3IP3 signaling axis that links promoter-specific chromatin remodeling to persistent ERK activation in GBM. In the available clinical glioma specimens spanning different WHO grades, P300 and TRAF3IP3 protein expression levels were positively correlated, whereas transcriptomic analyses revealed distinct molecular subtype-dependent expression patterns for EP300 and TRAF3IP3. Mechanistically, the transcription factor SP1 facilitated the recruitment of P300 to the TRAF3IP3 promoter, where P300 histone acetyltransferase (HAT) activity maintained localized H3K27ac enrichment and promoted TRAF3IP3 transcription. TRAF3IP3 subsequently associated with MEK1 through its 240–436-amino-acid region, thereby facilitating downstream ERK activation. Disruption of this MEK1-binding region impaired TRAF3IP3-mediated ERK phosphorylation, supporting a functional requirement for the TRAF3IP3–MEK1 interaction. Functional rescue experiments further demonstrated that TRAF3IP3 is a critical downstream mediator of P300-driven ERK signaling and the proliferation, migration, and invasion of GBM cells. Consistently, pharmacological inhibition of P300/CBP HAT activity reduced H3K27ac enrichment at the TRAF3IP3 promoter, suppressed TRAF3IP3 expression, and attenuated ERK activation, whereas genetic silencing of TRAF3IP3 substantially attenuated P300-driven malignant phenotypes in vitro and tumor-promoting effects in a subcutaneous xenograft model. Collectively, these findings delineate an SP1/P300–TRAF3IP3/MEK1–ERK regulatory cascade that connects locus-specific epigenetic remodeling with oncogenic MAPK signaling and identifies this axis as a potential therapeutic vulnerability in GBM.