Epigenetic activation of CD274/PD-L1 by the MSL complex expands its role beyond dosage compensation

Here we demonstrate that MSL1, a key subunit of the complex directly activates CD274 transcription by recruiting MOF to its promoter region and promoting H4K16 acetylation. Bioinformatic analyses revealed strong correlations between MSL1 expression, immune cell infiltration, and enrichment of immune-related gene sets across multiple cancer types. CRISPR/Cas9-mediated knockout of MSL1 or MSL3 markedly suppressed CD274 expression, whereas MSL1 overexpression enhanced CD274 levels and upregulated downstream immune- and apoptosis-related genes, including <i>BIRC3</i> and <i>HLA-A</i>. Dual-luciferase reporter assays, ChIP-qPCR and ChIP-seq further confirmed MSL1 binding near the -700 bp region of the CD274 promoter. Collectively, these findings uncover a previously unrecognized epigenetic mechanism linking the MSL complex to CD274 transcriptional regulation and identify MSL1 as a potential target for enhancing immunotherapy efficacy.