Format

Send to

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

LIG4 mediates Wnt signalling-induced radioresistance.

Author information

1
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
2
Research Laboratory for Nuclear Reactors, Tokyo Institute of Technology, Tokyo 152-8550, Japan.
3
Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
4
Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center and MD Anderson Cancer Center, Houston, Texas 77030, USA.
5
Program in Genes and Development, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

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.

PMID:
27009971
PMCID:
PMC4820809
DOI:
10.1038/ncomms10994
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center