Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10994
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Funding
- Cancer Prevention and Research Institute of Texas [RP140563]
- National Institutes of Health [NCI R01 CA193297-01]
- Department of Defense Peer Reviewed Cancer Research Program [CA140572]
- Duncan Family Institute Research Program
- University Cancer Foundation [IRG-08-061-01]
- Center for Stem Cell and Developmental Biology (MD Anderson Cancer Center)
- Institutional Research Grant (MD Anderson Cancer Center)
- New Faculty Award (MD Anderson Cancer Center Support Grant)
- Metastasis Research Center Grant (MD Anderson Cancer Center)
- SPORE in ovarian cancer [P50 CA83639]
- NIH through the MD Anderson Cancer Center Support Grant [CA016672]
- Grants-in-Aid for Scientific Research [24390290, 15H02817] Funding Source: KAKEN
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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 beta-catenin. Wnt signalling enhances non-homologous end-joining repair in CRC, which is mediated by LIG4 transactivated by beta-catenin. During radiation-induced intestinal regeneration, LIG4 mainly expressed in the crypts is conditionally upregulated in ISCs, accompanied by Wnt/beta-catenin signalling activation. Importantly, among the DNA repair genes, LIG4 is highly upregulated in human CRC cells, in correlation with beta-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.
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