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Cancers 2016, 8(5), 52; doi:10.3390/cancers8050052

The MYC 3′ Wnt-Responsive Element Drives Oncogenic MYC Expression in Human Colorectal Cancer Cells

1
Department of Biochemistry & Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
2
Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
3
The Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Renée van Amerongen and Walter Birchmeier
Received: 1 April 2016 / Revised: 11 May 2016 / Accepted: 18 May 2016 / Published: 23 May 2016
(This article belongs to the Special Issue Wnt Signaling in Cancer)
View Full-Text   |   Download PDF [2740 KB, uploaded 23 May 2016]   |  

Abstract

Mutations in components of the Wnt/β-catenin signaling pathway drive colorectal cancer (CRC) by deregulating expression of downstream target genes including the c-MYC proto-oncogene (MYC). The critical regulatory DNA enhancer elements that control oncogenic MYC expression in CRC have yet to be fully elucidated. In previous reports, we correlated T-cell factor (TCF) and β-catenin binding to the MYC 3′ Wnt responsive DNA element (MYC 3′ WRE) with MYC expression in HCT116 cells. Here we used CRISPR/Cas9 to determine whether this element is a critical driver of MYC. We isolated a clonal population of cells that contained a deletion of a single TCF binding element (TBE) within the MYC 3′ WRE. This deletion reduced TCF/β-catenin binding to this regulatory element and decreased MYC expression. Using RNA-Seq analysis, we found altered expression of genes that regulate metabolic processes, many of which are known MYC target genes. We found that 3′ WRE-Mut cells displayed a reduced proliferative capacity, diminished clonogenic growth, and a decreased potential to form tumors in vivo. These findings indicate that the MYC 3′ WRE is a critical driver of oncogenic MYC expression and suggest that this element may serve as a therapeutic target for CRC. View Full-Text
Keywords: MYC; Wnt-responsive element; β-catenin; colorectal cancer MYC; Wnt-responsive element; β-catenin; colorectal cancer
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Rennoll, S.A.; Eshelman, M.A.; Raup-Konsavage, W.M.; Kawasawa, Y.I.; Yochum, G.S. The MYC 3′ Wnt-Responsive Element Drives Oncogenic MYC Expression in Human Colorectal Cancer Cells. Cancers 2016, 8, 52.

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