BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis. Issue 5 (14th January 2016)

• Record Type: Journal Article
• Authors: Parang, Bobak; Kaz, Andrew M; Barrett, Caitlyn W; Short, Sarah P; Ning, Wei; Keating, Cody E; Mittal, Mukul K; Naik, Rishi D; Washington, Mary K; Revetta, Frank L; Smith, J Joshua; Chen, Xi; Wilson, Keith T; Brand, Thomas; Bader, David M; Tansey, William P; Chen, Ru; Brentnall, Teresa A; Grady, William M; Williams, Christopher S
• Is Part Of: Gut. Volume 66:Issue 5(2017)
• Page Start: 852
• Page End: 862
• Publication Date: 2016-01-14
• Subjects: CANCER -- IBD -- ULCERATIVE COLITIS -- COLONIC NEOPLASMS -- COLORECTAL CANCER; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2015-310255
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: 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. Design: We determined BVES promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured BVES mRNA levels in a tissue microarray consisting of normal colons and CAC samples. Bves −/− 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. Results: BVES mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, BVES promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, Bves was underexpressed in experimental inflammatory carcinogenesis, and Bves −/− mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of Bves −/− 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. Conclusion: Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. BVES promoter methylation status may serve as a CAC biomarker.