LIG4 mediates Wnt signalling-induced radioresistance

Nat Commun. 2016 Mar 24;7:10994. doi: 10.1038/ncomms10994.

Abstract

Despite the implication of Wnt signalling in radioresistance, the underlying mechanisms are unknown. Here we find that high Wnt signalling 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 signalling 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/β-catenin signalling 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 signalling-induced radioresistance in CRC and ISCs, and further unveils the unexpected convergence between Wnt signalling and DNA repair pathways in tumorigenesis and tissue regeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Proliferation / radiation effects*
  • Cell Survival / genetics
  • Cell Survival / radiation effects
  • Colorectal Neoplasms / genetics*
  • Computer Simulation
  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair / genetics*
  • DNA Ligase ATP
  • DNA Ligases / genetics*
  • DNA Repair / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunohistochemistry
  • Intestinal Mucosa / metabolism
  • Intestines / cytology
  • Intestines / radiation effects*
  • Mice
  • Radiation Tolerance / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stem Cells / metabolism
  • Stem Cells / radiation effects*
  • Telomerase / genetics
  • Transcriptional Activation
  • Wnt Signaling Pathway / genetics
  • beta Catenin / metabolism

Substances

  • LIG4 protein, human
  • beta Catenin
  • Telomerase
  • Tert protein, mouse
  • DNA Ligases
  • DNA Ligase ATP