KAT8‐Low Osteosarcoma Suppresses Cisplatin Sensitivity via H4K16ac‐Mediated Cell Apoptosis

ABSTRACT Cisplatin (DDP), a core chemotherapeutic agent for osteosarcoma (OS), induces DNA cross‐linking to cause damage, yet the underlying regulatory mechanisms remain elusive. Our study has revealed that in DDP‐resistant osteosarcoma (OS) cells, both the expression level of the lysine acetyltransferase KAT8 and its mediated site‐specific acetylation of histone H4K16ac are significantly decreased. Using CUT&Tag technology and proteomic analysis, we demonstrated that the KAT8–H4K16ac axis modulates dynamic histone acetylation to epigenetically regulate DNA repair pathways. The biological inactivation of KAT8 results in a targeted decrease in the epigenetic mark H4K16ac at the promoter regions of genes associated with DNA repair, leading to diminished chromatin accessibility and inhibition of the p53 signaling pathway. Consequently, the DNA damage response is compromised, promoting cisplatin resistance in OS. In contrast, targeted restoration of H4K16ac reverses chemotherapy resistance through the reinstatement of chromatin dynamics and transcriptional activation of DNA repair programs. This hypothesis emphasizes the need to clarify the molecular mechanisms and signaling pathways associated with KAT8–H4K16ac, especially in relation to apoptotic pathways, which could offer new insights and justifications for treatment strategies in cisplatin‐resistant osteosarcoma.