LIG4 mediates Wnt signalling-induced radioresistance

Area of Science:

• Molecular Biology
• Cancer Research
• Gastroenterology

Background:

• Wnt signaling is implicated in radioresistance, but mechanisms remain unclear.
• Colorectal cancer (CRC) and intestinal stem cells (ISCs) exhibit radioresistance.
• Understanding these mechanisms is crucial for improving cancer therapy.

Purpose of the Study:

• To elucidate the molecular mechanisms linking Wnt signaling to radioresistance in CRC and ISCs.
• To identify key molecular players involved in this process.
• To explore potential therapeutic targets for overcoming radioresistance.

Main Methods:

• Investigated Wnt signaling activity in CRC cells and ISCs.
• Assessed the role of LIG4, a DNA repair enzyme, as a target of β-catenin.
• Utilized gene expression analysis and functional assays to determine LIG4's role in DNA repair and radioresistance.
• Examined LIG4 expression in human CRC tissues.

Main Results:

• High Wnt signaling correlates with radioresistance in CRC cells and ISCs.
• LIG4 is a direct target of β-catenin and is upregulated by Wnt signaling.
• Wnt signaling enhances non-homologous end-joining DNA repair through β-catenin-mediated LIG4 transactivation.
• LIG4 is highly upregulated in human CRC and its blockade sensitizes cells to radiation.

Conclusions:

• Wnt signaling confers radioresistance in CRC and ISCs by enhancing DNA double-strand break repair via LIG4.
• LIG4 represents a potential therapeutic target to overcome radioresistance in colorectal cancer.
• This study reveals a convergence between Wnt signaling and DNA repair pathways in cancer and tissue regeneration.