CDK1 Phosphorylates KAT8 at Ser348 to Stabilize the MSL Complex and Promote H4K16 Acetylation in Non-Small Cell Lung...

Cyclin-dependent kinase 1 (CDK1) is frequently upregulated in multiple cancers and plays a central role in cell cycle progression and tumorigenesis. However, whether CDK1 directly regulates the histone acetyltransferase KAT8 (also known as MOF) in non-small cell lung cancer (NSCLC) remains unclear. Here, we identify CDK1 as a kinase that directly interacts with and phosphorylates KAT8 at serine 348 (S348) and threonine 418 (T418). Mechanistically, CDK1-mediated phosphorylation, particularly at S348, enhances the interaction between KAT8 and MSL1, thereby stabilizing the MSL complex and promoting KAT8-dependent acetylation of histone H4 at lysine 16 (H4K16). Functionally, the phosphorylation-deficient mutant KAT8-S348A exhibits impaired MSL complex assembly, reduced H4K16 acetylation, and decreased NSCLC cell proliferation both in vitro and in vivo. Pharmacological inhibition of CDK1 using RO-3306 suppresses KAT8 phosphorylation and H4K16 acetylation, leading to significant tumor growth inhibition. Notably, this effect is partially rescued by re-expression of wild-type KAT8 but not by the S348A mutant, supporting a phosphorylation-dependent mechanism. Collectively, these findings define a CDK1-KAT8 signaling axis that promotes NSCLC proliferation through epigenetic regulation and suggest that targeting CDK1-dependent KAT8 phosphorylation may represent a potential therapeutic strategy for lung cancer.