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.

Quiescence Exit of Tert+ Stem Cells by Wnt/β-Catenin Is Indispensable for Intestinal Regeneration

“…Nonetheless, quiescent ISCs need to be further validated given the various expression of Lgr5 in the crypts. To overcome the current technical limitation in studying SCs, we recently generated a Tert knock-in mouse model (Jun, et al, 2016). Tert, a catalytic subunit of telomerase, is specifically expressed in self-renewing cells including SCs, germ cells, and cancer cells (Flores, et al, 2006).…”

The Role of Canonical Wnt Signaling in Regulating Radioresistance

“…Table 1 lists some of the small molecules that inhibit the Wnt pathway. As examples, iCRT14 enhances radiosensitivity in colon cancer [5] and FH535 promotes esophageal cancer radiosensitization [88]. These data illustrate that Wnt signaling is a good target for radiosensitization, and that a Wnt signaling inhibitor may be appropriate to test in future clinical trials.…”

“…For example, β-catenin promotes LIG4 expression in a p53-independent manner [5], thus promoting the NHEJ-mediated repair of DSBs. β-catenin also upregulates KU70/KU80 by regulating cyclooxygenase 2 and AMP-activated protein kinase in response to IR [70].…”

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

“…This is in agreement with numerous studies showing that gain-of-function mutations in β-catenin signaling and loss of α-catenin regulation are prevalent in cancer (Aaltomaa et al, 1999;Anttila et al, 1998;Clevers and Nusse, 2012;Gofuku et al, 1999;Lifschitz-Mercer et al, 2001;Matsui et al, 1994;Nakopoulou et al, 2002;Polakis, 2000;Richmond et al, 1997;Rimm et al, 1995;Shiozaki et al, 1994;Silvis et al, 2011;Tanaka et al, 2003;van Oort et al, 2007;Yang et al, 2006). This additional level of regulation by α-catenin may help explain why WNT stimulation has been reported to decrease the sensitivity of cells to DNA damage despite increased nuclear β-catenin levels (Chandra et al, 2015;Chen et al, 2007;Jun et al, 2016;Woodward et al, 2007), and why different experimental systems have had confounding results (Chevillard-Briet et al, 2014;Orford et al, 1999;Tao et al, 2015;Watson et al, 2010). Intriguingly, p53 is able to regulate WNT ligand production in a cell type-dependent manner (Lee et al, 2010) as well as β-catenin levels (Kim et al, 2011; Sadot Our results suggest that the effect of WNT stimulation on the DNA damage response may depend on the levels of nuclear α-catenin, as well as those of β-catenin and other proteins recruited to this complex.…”