O‐ GlcNAcylation of KAT2A Enhances Bladder Cancer Proliferation by Inhibiting the KAT2A ‐ TRIM22 Interaction

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Lysine acetyltransferase 2A (KAT2A) is a transcriptional coactivator and a member of the Histone Acetyltransferase (HAT) family. While altered KAT2A activity has been implicated in various cancers, its role in bladder cancer (BLCA) remains poorly understood. Post-translational modifications (PTMs), such as O-GlcNAcylation, play a critical role in cancer biology. In this study, we investigated the impact of O-GlcNAcylation on KAT2A stability and its oncogenic potential in BLCA. We analyzed 96 paired BLCA and normal tissue samples using quantitative real-time PCR (qPCR) and immunohistochemistry to assess KAT2A expression. Functional assays, including siRNA-mediated knockdown, co-immunoprecipitation (co-IP), ubiquitination, and chromatin immunoprecipitation (ChIP), were conducted in BLCA cell lines and xenograft models to understand KAT2A O-GlcNAcylation mechanisms. We found that KAT2A expression was significantly increased in BLCA tissues. O-GlcNAcylation at serine 583 (S583) stabilized KAT2A by inhibiting TRIM22-mediated ubiquitination. Hyper-O-GlcNAcylation increased H3K9 acetylation and upregulated oncogenes like TGFB1, E2F1, and GPX4, promoting cell proliferation and tumor growth. Mutation of S583 destabilized KAT2A, impaired H3K9 acetylation, and suppressed oncogene expression. Our results highlight the pivotal role of KAT2A in BLCA and demonstrate that O-GlcNAcylation at S583 is a crucial regulatory mechanism driving tumor progression. Targeting KAT2A O-GlcNAcylation may provide a promising therapeutic strategy for BLCA patients.

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