LIG4 Mediates Wnt Signalling-induced Radioresistance

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Mar 25

PMID 27009971

Citations 63

Authors

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

Jae-Il Park

Affiliations

Soon will be listed here.

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.

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