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

Authors: Parang, B.; Kaz, A. M.; Barrett, C. W.; Short, S. P.; Ning, W.; Keating, C. E.; Mittal, M. K.; Naik, R. D.; Washington, M. K.; Revetta, F. L.; Smith, J. J.; Chen, X.; Wilson, K. T.; Brand, T.; Bader, D. M.; Tansey, W. P.; Chen, R.; Brentnall, T. A.; Grady, W. M.; Williams, C. S.
Article Title: BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis
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 twohybrid 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.
Journal Title: Gut
Volume: 66
Issue: 5
ISSN: 0017-5749
Publisher: BMJ Publishing Group Ltd.  
Date Published: 2017-05-01
Start Page: 852
End Page: 862
Language: English
DOI: 10.1136/gutjnl-2015-310255
PROVIDER: scopus
PMCID: PMC5385850
PUBMED: 28389570
Notes: Article -- Export Date: 1 June 2017 -- Source: Scopus
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MSK Authors
  1. Jesse Joshua Smith
    138 Smith