<scp>KAT2A</scp> ‐ <scp>H3K79succ</scp> ‐Mediated <scp>SH2B3</scp> Upregulation Promotes <scp>TNBC</scp> Metastasis Through Diminishing the Ubiquitin‐Dependent Degradation of Vimentin

Triple-negative breast cancer (TNBC) is the most aggressive subtype among all breast cancer subtypes, attributed to the paucity of available targeted therapeutics. Lysine acetyltransferase 2A (KAT2A), an indispensable catalytic constituent of the transcriptional regulatory complex, has been implicated in the pathogenesis and progression of multiple malignancies. Nevertheless, the role of H3K79 site succinylation (H3K79succ) catalyzed by KAT2A in TNBC remains enigmatic. This study assessed the functional role of KAT2A in TNBC pathogenesis through colony formation assays, CCK-8 assay, wound healing assays, and transwell invasion assays. BALB/c nude mice were employed to establish models for studying the proliferation and metastasis of TNBC in vivo. Transcriptome sequencing (RNA-seq) combined with chromatin immunoprecipitation sequencing (ChIP-seq) and Luciferase reporter assays were conducted to identify the direct transcriptional target of KAT2A-catalyzed H3K79succ-SH2B adaptor 3 (SH2B3). Mass spectrometry and co-immunoprecipitation (Co-IP) assays were designed to investigate the mechanism of SH2B3 involved in promoting aggressiveness. Altogether, our study indicated that KAT2A modulates the malignant phenotype of TNBC by mediating H3K79succ to regulate the transcription of the SH2B3 gene, and the KAT2A/SH2B3/vimentin axis might be the potential molecular targets for diagnosing and treating TNBC.