BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis.

Abstract

Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD. We determined <i>BVES</i> promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured <i>BVES</i> mRNA levels in a tissue microarray consisting of normal colons and CAC samples. <i>Bves^-/-</i> and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels. <i>BVES</i> mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, <i>BVES</i> promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, <i>Bves</i> was underexpressed in experimental inflammatory carcinogenesis, and <i>Bves^-/-</i> mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of <i>Bves</i>^-/- tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction. Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. <i>BVES</i> promoter methylation status may serve as a CAC biomarker.