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Open AccessArticle

MYC Regulates α6 Integrin Subunit Expression and Splicing Under Its Pro-Proliferative ITGA6A Form in Colorectal Cancer Cells

1
Laboratory of Intestinal Physiopathology, Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
2
Laboratory of Pathology, Cancer Molecular Pathology Section, National Cancer Institute, Bethesda, MD 20892, USA
*
Author to whom correspondence should be addressed.
Present address: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0380, USA.
Cancers 2018, 10(2), 42; https://doi.org/10.3390/cancers10020042
Received: 3 January 2018 / Revised: 29 January 2018 / Accepted: 31 January 2018 / Published: 3 February 2018
(This article belongs to the Special Issue Integrins in Cancer)
The α6 integrin subunit (ITGA6) pre-mRNA undergoes alternative splicing to form two splicing variants, named ITGA6A and ITGA6B. In primary human colorectal cancer cells, the levels of both ITGA6 and β4 integrin subunit (ITGB4) subunits of the α6β4 integrin are increased. We previously found that the upregulation of ITGA6 is a direct consequence of the increase of the pro-proliferative ITGA6A variant. However, the mechanisms that control ITGA6 expression and splicing into the ITGA6A variant over ITGA6B in colorectal cancer cells remain poorly understood. Here, we show that the promoter activity of the ITGA6 gene is regulated by MYC. Pharmacological inhibition of MYC activity with the MYC inhibitor (MYCi) 10058-F4 or knockdown of MYC expression by short hairpin RNA (shRNA) both lead to a decrease in ITGA6 and ITGA6A levels in colorectal cancer cells, while overexpression of MYC enhances ITGA6 promoter activity. We also found that MYC inhibition decreases the epithelial splicing regulatory protein 2 (ESRP2) splicing factor at both the mRNA and protein levels. Chromatin immunoprecipitation revealed that the proximal promoter sequences of ITGA6 and ESRP2 were occupied by MYC and actively transcribed in colorectal cancer cells. Furthermore, expression studies in primary colorectal tumors and corresponding resection margins confirmed that the up-regulation of the ITGA6A subunit can be correlated with the increase in MYC and ESRP2. Taken together, our results demonstrate that the proto-oncogene MYC can regulate the promoter activation and splicing of the ITGA6 integrin gene through ESRP2 to favor the production of the pro-proliferative ITGA6A variant in colorectal cancer cells. View Full-Text
Keywords: colorectal cancer; MYC; integrin α6β4; ITGA6; alternative splicing; ESRP2 colorectal cancer; MYC; integrin α6β4; ITGA6; alternative splicing; ESRP2
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MDPI and ACS Style

Groulx, J.-F.; Boudjadi, S.; Beaulieu, J.-F. MYC Regulates α6 Integrin Subunit Expression and Splicing Under Its Pro-Proliferative ITGA6A Form in Colorectal Cancer Cells. Cancers 2018, 10, 42.

AMA Style

Groulx J-F, Boudjadi S, Beaulieu J-F. MYC Regulates α6 Integrin Subunit Expression and Splicing Under Its Pro-Proliferative ITGA6A Form in Colorectal Cancer Cells. Cancers. 2018; 10(2):42.

Chicago/Turabian Style

Groulx, Jean-François; Boudjadi, Salah; Beaulieu, Jean-François. 2018. "MYC Regulates α6 Integrin Subunit Expression and Splicing Under Its Pro-Proliferative ITGA6A Form in Colorectal Cancer Cells" Cancers 10, no. 2: 42.

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