PO-354 Disrupting the acetylation of ISX-BRD4 by p300/CBP-associated factor (PCAF) suppresses tumour metastasis

Abstract

IntroductionThe epithelial–mesenchymal transition (EMT) is an important process in the progression of cancer, but its occurrence and the regulatory mechanism are not fully understood.Material and methodsIn this study, Intestine specific homeobox (ISX) acted both as an proto-oncogene and upstream regulator of EMT markers, by which modulates tumorigenic initiation and progression in lung cancer cells.Results and discussionsMechanistically, ISX acetylated by p300/CBP- associated factor (PCAF) recruits chromatin reader, bromodomain- containing protein 4 (BRD4), to initiate chromatin remodelling, and upregulated EMT downstream regulators in tumours cells. Ectopic expression of ISX were shown to enhance TWIST1, Snail1, vascular endothelial growth factor (VEGF) expression by recruiting BRD4 to enhance Pol II-dependent transcription, leading to remodelling of the tumour microenvironment. Neutralising VEGF by avastin effectively abrogates metastasis induced by the ISX-BRD4 complex. In NSCLC carcinoma samples, significantly increased ISX expression was noted, correlating with distinct clinical metastatic features and poor prognosis.ConclusionThese results suggest that the ISX-BRD4 axis mediates EMT signalling and exerts significant regulatory effects on tumour initiation and metastasis.