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

Area of Science:

• Molecular Biology
• Oncology
• Genetics

Background:

• Wnt/β-catenin signaling pathway mutations drive colorectal cancer (CRC) by altering gene expression.
• The c-MYC proto-oncogene (MYC) is a key oncogene in CRC, but its regulatory elements are not fully understood.
• Previous studies linked T-cell factor (TCF) and β-catenin binding to the MYC 3' Wnt responsive DNA element (MYC 3' WRE) with MYC expression in CRC cells.

Purpose of the Study:

• To investigate the role of the MYC 3' WRE as a critical driver of oncogenic MYC expression in CRC.
• To determine if the MYC 3' WRE is a potential therapeutic target for colorectal cancer.

Main Methods:

• CRISPR/Cas9 gene editing was used to create a deletion in a TCF binding element (TBE) within the MYC 3' WRE.
• Analysis of TCF/β-catenin binding, MYC expression, and gene expression profiles (RNA-Seq) in edited cells.
• Assessment of cellular proliferation, clonogenic growth, and tumor formation in vivo.

Main Results:

• Deletion of a single TBE within the MYC 3' WRE reduced TCF/β-catenin binding and decreased MYC expression.
• RNA-Seq revealed altered expression of metabolic genes, many of which are known MYC targets.
• Edited cells exhibited reduced proliferation, diminished colony formation, and decreased tumorigenicity.

Conclusions:

• The MYC 3' WRE is a critical regulatory element driving oncogenic MYC expression in CRC.
• The MYC 3' WRE represents a potential therapeutic target for colorectal cancer treatment.