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

Bobak Parang, Andrew M. Kaz, Caitlyn W. Barrett, Sarah P. Short, Wei Ning, Cody E. Keating, Mukul K. Mittal, Rishi D. Naik, Mary K. Washington, Frank L. Revetta, J. Joshua Smith, Xi Chen, Keith T. Wilson, Thomas Brand, David M. Bader, William P. Tansey, Ru Chen, Teresa A. Brentnall, William M. Grady, Christopher S. Williams

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)852-862
Number of pages11
JournalGut
Volume66
Issue number5
DOIs
StatePublished - Jan 14 2016

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Colitis
Blood Vessels
Neoplasms
Azoxymethane
Dextran Sulfate
Methylation
Tight Junction Proteins
Protein Phosphatase 2
Messenger RNA
myc Genes
Tumor Biomarkers
Colon
Carcinogenesis
Mucous Membrane
Yeasts
Cell Line

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Parang, B., Kaz, A. M., Barrett, C. W., Short, S. P., Ning, W., Keating, C. E., ... Williams, C. S. (2016). BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis. Gut, 66(5), 852-862. https://doi.org/10.1136/gutjnl-2015-310255

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

In: Gut, Vol. 66, No. 5, 14.01.2016, p. 852-862.

Research output: Contribution to journalArticle

Parang, B, Kaz, AM, Barrett, CW, Short, SP, Ning, W, Keating, CE, Mittal, MK, Naik, RD, Washington, MK, Revetta, FL, Smith, JJ, Chen, X, Wilson, KT, Brand, T, Bader, DM, Tansey, WP, Chen, R, Brentnall, TA, Grady, WM & Williams, CS 2016, 'BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis', Gut, vol. 66, no. 5, pp. 852-862. https://doi.org/10.1136/gutjnl-2015-310255
Parang B, Kaz AM, Barrett CW, Short SP, Ning W, Keating CE et al. BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis. Gut. 2016 Jan 14;66(5):852-862. https://doi.org/10.1136/gutjnl-2015-310255
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. / BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis. In: Gut. 2016 ; Vol. 66, No. 5. pp. 852-862.
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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.",
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T1 - BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis

AU - Parang, Bobak

AU - Kaz, Andrew M.

AU - Barrett, Caitlyn W.

AU - Short, Sarah P.

AU - Ning, Wei

AU - Keating, Cody E.

AU - Mittal, Mukul K.

AU - Naik, Rishi D.

AU - Washington, Mary K.

AU - Revetta, Frank L.

AU - Smith, J. Joshua

AU - Chen, Xi

AU - Wilson, Keith T.

AU - Brand, Thomas

AU - Bader, David M.

AU - Tansey, William P.

AU - Chen, Ru

AU - Brentnall, Teresa A.

AU - Grady, William M.

AU - Williams, Christopher S.

PY - 2016/1/14

Y1 - 2016/1/14

N2 - 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.

AB - 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.

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