DDX5 super-enhancer promotes vasculogenic mimicry formation and metastasis in nasopharyngeal carcinoma by enhancing ADAM10 transcription.

Anti-angiogenic therapies (AATs) exhibit limited efficacy, as most patients with cancer inevitably develop resistance to them. In this study, data generated using a nasopharyngeal carcinoma orthotopic mouse model, combined with clinical data, reveal compensatory vasculogenic mimicry (VM) formation during AAT treatment and the association of VM with poor prognosis in nasopharyngeal carcinoma. Additionally, data-independent acquisition mass spectrometry-based proteomics shows that upregulation of a disintegrin And metalloprotease 10 (ADAM10) contributes to VM. Mechanistically, epigenetic and high-resolution chromatin interaction landscape analyses demonstrate that although ADAM10 does not interact with either the proximal or distal enhancers, DEAD-box helicase 5 (DDX5), a transcription factor of ADAM10, is regulated by long-range looping enhancer-promoter interactions. Further analyses identify transcription factors binding to critical constituents of the DDX5 super-enhancer. Ingenol mebutate, which docks excellently with DDX5, reverses ADAM10-mediated gene expression changes, thereby effectively suppressing compensatory VM formation and metastasis and improving prognosis. Collectively, these findings provide insights into the clinical application of AATs.