The MYC 3′ Wnt-responsive element drives oncogenic MYC expression in human colorectal cancer cells

Sherri A. Rennoll, Melanie A. Eshelman, Wesley M. Raup-Konsavage, Yuka Imamura Kawasawa, Gregory S. Yochum

Research output: Contribution to journalArticle

9 Scopus citations

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 31 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.

Original languageEnglish (US)
Article number52
JournalCancers
Volume8
Issue number5
DOIs
StatePublished - May 23 2016

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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