The KAT8-CDK1 K33 acetylation axis drives doxorubicin resistance by suppressing ferroptosis and apoptosis in breast cancer

Abstract

Doxorubicin (Dox) resistance severely limits therapeutic efficacy in breast cancer, yet the epigenetic mechanisms linking cell-cycle control to therapy-induced cell death remain unclear. Here, we identify the histone acetyltransferase KAT8 as a critical driver of Dox resistance. Transcriptomic analysis of neoadjuvant cohorts revealed elevated KAT8 expression in residual disease (RD) tumors, which was validated in an independent cohort of 95 patients. High KAT8 levels correlated with poor therapeutic response. Mechanistically, KAT8 directly acetylated CDK1 at lysine 33 (K33) in Dox-resistant MCF-7/ADR and MDA-MB-231/ADR cells. K33 acetylation sustained CDK1 phosphorylation at T14, Y15, and T161, maintaining kinase activity under chemotherapeutic stress. Disruption of KAT8, either by genetic silencing or pharmacological inhibition with MG149, reduced CDK1 activation, increased mitochondrial depolarization and oxidative stress, and restored Dox sensitivity. Functionally, KAT8-dependent CDK1 K33 acetylation suppressed both apoptosis and ferroptosis, two principal Dox-induced cell death pathways. Re-expression of wild-type CDK1, but not the acetylation-deficient K33R mutant, rescued chemoresistance. In vivo, MG149 co-treatment or expression of CDK1-K33R significantly enhanced Dox-mediated tumor suppression in xenograft models without overt toxicity. Together, these findings establish KAT8-dependent CDK1 K33 acetylation as a key epigenetic mechanism sustaining anthracycline resistance and suggest that targeting the KAT8-CDK1 axis may provide a therapeutic strategy to overcome refractory breast cancer.