title: LIG4 mediates Wnt signalling-induced radioresistance.
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.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Sohee
authors.initials: S
authors.lastname: Jun
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Youn-Sang
authors.initials: YS
authors.lastname: Jung
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Han Na
authors.initials: HN
authors.lastname: Suh
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Moon Jong
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Young Sun
authors.initials: YS
authors.lastname: Oh
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Esther M
authors.initials: EM
authors.lastname: Lien
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Shen
authors.affiliation: Research Laboratory for Nuclear Reactors, Tokyo Institute of Technology, Tokyo 152-8550, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center and MD Anderson Cancer Center, Houston, Texas 77030, USA.|Program in Genes and Development, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Pierre D
authors.initials: PD
authors.lastname: McCrea
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center and MD Anderson Cancer Center, Houston, Texas 77030, USA.|Program in Genes and Development, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center and MD Anderson Cancer Center, Houston, Texas 77030, USA.|Program in Genes and Development, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center and MD Anderson Cancer Center, Houston, Texas 77030, USA.|Program in Genes and Development, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Park
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000528:radiation effects*; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000235:genetics*; D003198:Computer Simulation; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000235:genetics*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000528:radiation effects*; D051379:Mice; D011836:Radiation Tolerance / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism / Q000528:radiation effects*; D019098:Telomerase / Q000235:genetics; D015533:Transcriptional Activation; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: C000607893:LIG4 protein, human; D051176:beta Catenin; D019098:Telomerase; C509187:Tert protein, mouse; D011088:DNA Ligases; D000072481:DNA Ligase ATP