KAT6 acetyltransferases as emerging therapeutic targets in cancer

KAT6A and KAT6B are MYST-family chromatin regulators that function as catalytic subunits of multiprotein acetyltransferase complexes to maintain transcriptional programs defining cellular lineage identity. Rather than acting through recurrent activating point mutations, KAT6 proteins are most often co-opted in cancer through gene fusion, copy number gain, sustained overexpression, or tumor reliance on their activity, creating context-specific chromatin dependencies that sustain malignant identity. Through deposition of histone H3 acetylation marks, most prominently H3K23ac in oncogenic contexts, and coordination of transcriptional coactivators, KAT6 complexes reinforce transcriptional programs governing stemness, hormone signaling, immune suppression, and cellular differentiation states. Recent advances demonstrate that the KAT6 catalytic pocket is druggable, enabling sustained suppression of oncogenic transcriptional programs in preclinical models and early clinical studies, particularly in estrogen receptor-positive breast cancer. Here, we synthesize current understanding of KAT6 complex biology, tumor-specific mechanisms, emerging catalytic and protein-targeting therapeutic strategies, and the biomarker and combination approaches that will be needed to determine where KAT6 inhibition can be most effectively translated in cancer.