Tong Sha, Kun Jiao, Jianing Li, Ye Zheng, Linbin Wang, Zhi Cui
Oral squamous cell carcinoma (OSCC) is an aggressive head and neck malignancy. Lysine acetyltransferase 2B (KAT2B) exerts tumor-suppressive functions in various cancers, yet its function in OSCC remains unclear. Through integrative analysis of five public transcriptomic datasets with validation in clinical tissues and cell lines, we identified a consistent reduction of KAT2B expression in OSCC. Functional assays demonstrated that KAT2B overexpression inhibited OSCC cell proliferation, tumorsphere formation, stemness marker expression, and in vivo tumor growth, whereas KAT2B silencing produced opposite effects. Furthermore, KAT2B overexpression enhanced RSL-3-induced ferroptosis, evidenced by increased Fe2+ accumulation, elevated lipid reactive oxygen species (ROS) levels, aggravated mitochondrial damage, and reduced GPX4 protein; conversely, KAT2B knockdown conferred ferroptosis resistance. Mechanistically, integrating mRNA sequencing with the FerrDb database identified glutathione S-transferase zeta 1 (GSTZ1) (log2FC = 1.44, p < 0.001) as a key downstream target of KAT2B in ferroptosis regulation. ChIP-qPCR confirmed that KAT2B transcriptionally activates GSTZ1 by enhancing histone H3 lysine 9 acetylation (H3K9ac) enrichment at its promoter. Rescue assays further confirmed that depletion of GSTZ1 counteracted the effects of KAT2B overexpression on OSCC cell proliferation and ferroptosis. Collectively, we find that KAT2B transcriptionally activates GSTZ1 in a H3K9ac-dependent manner, which in turn inhibits GPX4 expression, thereby suppressing OSCC proliferation and stemness while enhancing ferroptosis sensitivity. This defines the KAT2B-GSTZ1 axis as a novel tumor-suppressive mechanism and an emerging therapeutic target for OSCC.