The tumor suppressor gene rap1GAP is silenced by mir-101-mediated EZH2 overexpression in invasive squamous cell carcinoma

Rap1GAP is a critical tumor suppressor gene that is down-regulated in multiple aggressive cancers such as head and neck squamous cell carcinoma, melanoma and pancreatic cancer. However, the mechanistic basis of rap1GAP down-regulation in cancers is poorly understood. By employing an integrative approach, we demonstrate polycomb mediated repression of rap1GAP that involves EZH2, a histone methyltransferase in head and neck cancers. We further demonstrate that the loss of miR-101 expression correlates with EZH2 up-regulation, and the concomitant down-regulation of rap1GAP in head and neck cancers. EZH2 represses rap1GAP by facilitating the trimethylation of H3K27, a mark of gene repression, and also hypermethylation of rap1GAP promoter. These results provide a conceptual framework involving a microRNA-oncogene-tumor suppressor axis to understand head and neck cancer progression.