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 tumorigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function, and its relevance to inflammatory bowel disease (IBD) patients. Design We determined BVES promoter methylation status using an Infinium HumanMethylation450 array screen of patients with ulcerative colitis 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 tumor formation. Lastly, we utilized 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 tumors 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 tumor multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of Bves−/− tumors revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signaling pathway whereby BVES interacts with PR61α, a PP2A regulatory subunit, to mediate c-Myc destruction. Conclusions Loss of BVES promotes inflammatory tumorigenesis through dysregulation of Wnt signaling and the oncogene c-Myc. BVES promoter methylation status may serve as a CAC biomarker.

The Role of the Popeye Domain Containing Gene Family in Organ Homeostasis

“…To date, evidence on the effects of POPDC1 on cell proliferation and its interaction with molecules in pathways that regulate cell proliferation such as Zonula occludens-1 (ZO-1), Wnt and c-Myc, are consistent with POPDC1 being a regulator of cell proliferation and its loss or suppression of function enhancing malignant cell behavior [7,10,41,42]. The loss of POPDC1 function has further been shown to enhance cell migration, proliferation, and invasion in many solid tumors [10,37,38,[42][43][44]. Furthermore, POPDC1 expression is significantly suppressed at all clinical stages of breast [43] and gastric cancer [45] without correlation to clinical progression.…”

“…The protein is tethered to the plasma membrane as a dimer that in the case of POPDC1 is stabilized by a disulfide bridge. The Popeye domain serves as a specific high-affinity binding site for cAMP [10].…”

“…Activation of the Wnt pathway regulates multiple cellular processes including cell proliferation, cell cycle arrest, apoptosis and tissue homeostasis [76,77]. Dysregulation of Wnt signaling is thus a driving force of tumorigenesis [7,10]. Activation of the canonical Wnt signaling pathway (also known as the Wnt/β-catenin pathway) causes the cytoplasmic accumulation of β-catenin and its subsequent translocation into the nucleus [76,77].…”

Blood Vessel Epicardial Substance (BVES) in junctional signaling and cancer

“…Parang et al conducted the first in vivo study testing BVES as a tumor modifier. 54 Using the wellestablished azoxymethane repeated cycles of dextran sodium sulfate (AOM/DSS) 55-58 model of inflammatory carcinogenesis, they showed that Bves-/-mice developed worse inflammatory injury, greater tumor multiplicity, and a higher degree of intratumoral dysplasia. The authors observed increased intratumoral Wnt signaling at the protein level.…”

“…Interestingly, they showed that the BVES promoter was also hypermethylated in distant, non-malignant mucosa of patients who also had colitis-associated cancer, suggesting that BVES promoter methylation status could be used a biomarker of distant cancer. 54 The current method of cancer screening in inflammatory bowel disease patients, who are at a significantly elevated risk of developing colitisassociated cancer, 69 is surveillance colonoscopy, in which the colon is biopsied with the hope that cancer can detected at an early and therefore treatable stage. However, the screening for malignancy in the colon of inflammatory bowel disease patients can be challenging because the lesions are frequently flat, making it difficult to identify, especially in the setting of inflammatory changes.…”