Abstract
Lysine acetyltransferase 6 (KAT6) consists of KAT6A and its paralog KAT6B, which represent crucial regulators for epigenetic modifications. By acylating histone H3 and nonhistone proteins, KAT6 enzymes play predominant roles in transcription, cell cycle, diverse developmental processes, regulation of the immune system, and self-renewal and maintenance of hematopoietic and neural stem cells. Importantly, the frequent molecular dysregulation of KAT6A and KAT6B correlates with survival outcomes of cancers, contributing to the exploration of a wide array of small-molecule inhibitors against KAT6 catalytic activity. Recent progress in drug discovery has led to the development of dual KAT6A and KAT6B inhibitors with potent antitumor efficacy and selectivity in both preclinical and clinical settings, supporting KAT6 as a druggable, promising target for the treatment of cancers, particularly breast cancers. In this review, we summarize the currently available information regarding the physiological and pathological functions of KAT6A and KAT6B and discuss their potential as antitumor targets in drug development. We also present the discovery and development of an emerging class of KAT6 inhibitors under investigation for breast cancer, along with potential molecular mechanisms underlying the therapeutic efficacy of targeting KAT6, providing references for developing therapeutic strategies in clinical practice.