BackgroundAberrant ubiquitin-proteasome system (UPS) triggers various disorders of biological events and contributes to progression of tumorigenesis. The tripartite motif containing 22 (TRIM22) was demonstrated to participate in the progression of multiple malignancies. Nevertheless, the role of TRIM22 in melanoma is still indefinite. This project aims to investigate the biological function of TRIM22 in melanoma and provide novel therapeutical targets.MethodsBioinformatic algorithms were used to investigate prognostic significance of TRIM22. The in vitro or in vivo assays were used to explore the functions of TRIM22 in melanoma. The Co-Immunoprecipitation (Co-IP) and in vivo ubiquitination assays were used to assess regulations of TRIM22 on lysine acetyltransferase 2 A (KAT2A). The Chromatin immunoprecipitation (ChIP) assays and luciferase reporter assay were utilized to explore epigenetic regulations of KAT2A on Notch1.ResultsHere, we utilized the bioinformatic methods to confirm that TRIM22 is decreased in melanoma than normal tissues. Patients with low TRIM22 levels had shorter survival months than those with high TRIM22 levels. Targeting TRIM22 favors melanoma cell migration, proliferation, and tumor development in vitro and in vivo. Mechanistically, TRIM22 interacts with KAT2A and promotes its degradation in a ubiquitination-dependent manner. Melanoma cells with TRIM22 deficiency depended on KAT2A to enhance malignant progression, including proliferation, migration, and in vivo growth. KEGG analysis determined the positive correlation between KAT2A and Notch signaling. Chromatin Immunoprecipitation (ChIP) assays implicated that KAT2A directly binds to the promoter region of Notch1 and mediates the enrichment of H3K9ac modification. KAT2A activates Notch1 transcriptional levels and sustains the stemness feature of melanoma cells. Nocth1 inhibitor (IMR-1) effectively suppresses the growth of TRIM22lowmelanoma in vitro and in vivo but fails to inhibit TRIM22highmelanoma.ConclusionTogether, our study illustrates the mechanism by which the TRIM22-KAT2A-Notch1 axis promotes melanoma progression, and demonstrates that KAT2A/Nocth1 confers an epigenetic vulnerability in TRIM22lowmelanoma.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12967-023-04305-1.