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The transcriptional activation function of YAP in cancer development has been widely studied. However, the underlying regulatory mechanisms remain largely unknown. In this study, we found that EP300, one histone acetyltransferase, interacted with YAP and was recruited into the phase separated condensates of YAP. Transcriptomic analysis revealed substantial alterations in gene expression upon EP300 depletion, with downregulated genes associated with cancer progression and Hippo-YAP pathway. Notably, disruption of EP300 inhibited the transcriptional activation of YAP and reduced the binding of H3K27ac on YAP target oncogenes in Hippo pathway. Moreover, depletion of EP300 effectively inhibited YAP-driven tumor growth. Taken together, these results indicate that EP300 contributes to lung cancer progression by promoting the oncogenic transcription of YAP through H3K27ac, which suggests that YAP-EP300 axis may be potential therapeutic targets for lung cancer treatment. • EP300 interacts with YAP and is recruited into the phase separated condensates of YAP. • Depletion of EP300 suppresses the oncogenic transcription of YAP target genes in Hippo pathway. • Inhibition of EP300 reduces the binding of H3K27ac on YAP target genes. • Blockade of EP300 suppresses YAP-driven tumor growth. [ABSTRACT FROM AUTHOR]