p300 (E1A binding protein 300) and CBP (CREB-binding protein) are critical regulators of chromatin dynamics and gene expression, playing essential roles in various cellular processes, including proliferation, differentiation, apoptosis, and immune responses. These homologous histone acetyltransferases (HATs) function as transcriptional co-activators by acetylating histones and non-histone proteins. p300/CBP is essential for development, and dysregulation of p300 and CBP has been implicated in several human diseases, particularly cancer. Somatic mutations that inactivate p300/CBP are frequently observed across various cancer types. Additionally, other mutations leading to translocations or truncations of p300/CBP can result in enhanced catalytic activity, potentially representing novel gain-of-function mutations that promote tumor progression. In this review, we discuss the mechanisms underlying the regulation of p300/CBP HAT activity, its dysregulation in cancer, and the development of p300/CBP inhibitors and their potential in cancer therapies.
