Targeting the transcriptional coactivator p300/CBP in cancer: Mechanistic insights and translational implications for...

The transcriptional coactivators p300 and CREB-binding protein (CBP) have emerged as central regulators of enhancer-mediated transcription and key epigenetic integrators of oncogenic signaling in cancer. Through their histone acetyltransferase activity, particularly the deposition of histone H3 lysine 27 acetylation (H3K27ac), p300/CBP control enhancer activation and coordinate transcriptional programs that govern cell identity, tumor progression, and therapeutic response. Dysregulation of enhancer activity is increasingly recognized as a fundamental mechanism driving oncogenic transcription across diverse malignancies. Recent advances in chemical biology have enabled pharmacological targeting of p300/CBP through several complementary strategies, including catalytic histone acetyltransferase (HAT) inhibitors, bromodomain (BRD) inhibitors, dual BET-p300 inhibitors, and emerging targeted protein degradation approaches. In this review, we summarize the molecular functions of p300/CBP, recent progress in the development of pharmacological agents targeting these coactivators, and the current landscape of clinical translation. Catalytic inhibition of p300/CBP directly suppresses H3K27ac and provides a measurable tumor pharmacodynamic biomarker, whereas alternative targeting modalities modulate enhancer-driven transcription through distinct molecular mechanisms. Early-phase clinical studies indicate that p300-directed agents can achieve pharmacodynamic modulation in patients. We further discuss the translational relevance of p300 targeting in osteosarcoma, a malignancy characterized by genomic instability and heterogeneous transcriptional states rather than dominant kinase mutations. Collectively, these findings position p300 catalytic inhibition as a mechanistically defined and pharmacologically tractable strategy for targeting enhancer-driven oncogenic transcription and support continued clinical development of p300-directed therapies.