LIG4 mediates Wnt signalling-induced radioresistance

Sohee Jun, Youn-Sang Jung, Han Na Suh, Wenqi Wang, Moon Jong Kim, Young Sun Oh, Esther M. Lien, Xi Shen, Yoshihisa Matsumoto, Pierre D. McCrea, Lei Li, Junjie Chen and Jae-Il Park ()
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Sohee Jun: The University of Texas MD Anderson Cancer Center
Youn-Sang Jung: The University of Texas MD Anderson Cancer Center
Han Na Suh: The University of Texas MD Anderson Cancer Center
Wenqi Wang: The University of Texas MD Anderson Cancer Center
Moon Jong Kim: The University of Texas MD Anderson Cancer Center
Young Sun Oh: The University of Texas MD Anderson Cancer Center
Esther M. Lien: The University of Texas MD Anderson Cancer Center
Xi Shen: The University of Texas MD Anderson Cancer Center
Yoshihisa Matsumoto: Research Laboratory for Nuclear Reactors, Tokyo Institute of Technology
Pierre D. McCrea: The University of Texas MD Anderson Cancer Center
Lei Li: The University of Texas MD Anderson Cancer Center
Junjie Chen: The University of Texas MD Anderson Cancer Center
Jae-Il Park: The University of Texas MD Anderson Cancer Center

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10994

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