Revealing how tissue stem cells and cancer stem cell-like cells are resistant to radiation

Despite the implication of Wnt signaling in radioresistance, the underlying mechanisms are unknown. We found that high Wnt signaling is associated with radioresistance in colorectal cancer (CRC) cells and intestinal stem cells (ISCs). We find that LIG4, a DNA ligase in DNA double-strand break repair, is a direct target of β-catenin. Wnt signaling enhances non-homologous end-joining repair in CRC, which is mediated by LIG4 transactivated by β-catenin. During radiation-induced intestinal regeneration, LIG4 mainly expressed in the crypts is conditionally upregulated in ISCs, accompanied by Wnt/b-catenin signaling activation. Importantly, among the DNA repair genes, LIG4 is highly upregulated in human CRC cells, in correlation with β-catenin hyperactivation. Furthermore, blocking LIG4 sensitizes CRC cells to radiation. Our results reveal the molecular mechanism of Wnt signaling-induced radioresistance in CRC and ISCs, and further unveils the unexpected convergence between Wnt signaling and DNA repair pathways in tumorigenesis and tissue regeneration. 

S Jun, YS Jung et al., Nature Communications 2016 (PDF)