Regulation of Wnt Singaling Pathway by Poly (ADP-Ribose) Glycohydrolase (PARG) Silencing Suppresses Lung Cancer in Mice Induced by Benzo(a)pyrene Inhalation Exposure

Abstract

Benzo(a)pyrene (BaP) is a polycyclic aromatic hydrocarbon that specifically causes cancer and is widely distributed in the environment. Poly (ADP-ribosylation), as a key post-translational modification in BaP-induced carcinogenesis, is mainly catalyzed by poly (ADP-ribose) glycohydrolase (PARG) in eukaryotic organisms. Previously, it is found that PARG silencing can counteract BaP-induced carcinogenesis in vitro , but the mechanism remained unclear. In this study, we further examined this process in vivo by using heterozygous PARG knockout mice (PARG +/− ). Wild-type and PARG +/− mice were individually treated with 0 or 10 μg/m 3 BaP for 90 or 180 days by dynamic inhalation exposure. Pathological analysis of lung tissues showed that, with extended exposure time, carcinogenesis and injury in the lungs of WT mice was progressively worse; however, the injury was minimal and carcinogenesis was not detected in the lungs of PARG +/− mice. These results indicate that PARG gene silencing protects mice against lung cancer induced by BaP inhalation exposure. Furthermore, as the exposure time was extended, the protein phosphorylation level was down-regulated in WT mice, but up-regulated in PARG +/− mice. The relative expression of Wnt2b and Wnt5b mRNA in WT mice were significantly higher than those in the control group, but there was no significant difference in PARG +/− mice. Meanwhile, the relative expression of Wnt2b and Wnt5b proteins, as assessed by immunohistochemistry and Western blot analysis, was significantly up-regulated by BaP in WT mice; while in PARG +/− mice it was not statistically affected. Our work provides initial evidence that PARG silencing suppresses BaP induced lung cancer and stabilizes the expression of Wnt ligands, PARG gene and Wnt ligands may provide new options for the diagnosis and treatment of lung cancer.

WNT signaling and AHCTF1 promote oncogenic MYC expression through super-enhancer-mediated gene gating

“…The PARP1 activity playing a role in colorectal [234,237] ad cervical carcinogenesis [235]. Accordingly, silencing PARG function suppressed cancer development induced Benzo(a)pyrene by in mice [238]. Auto-PARylation of the PARP-1 protein induced by DNA damage inhibited the functional interaction of PARP-1 with TCF-4 [237].…”

Targeting dePARylation for cancer therapy

“…Additionally, recent studies have indicated that increased PARG expression is associated with higher incidences of breast cancers as well as cellular transformation and invasion in vivo [94]. Moreover, PARG suppression has been implicated to prevent lung cancer in PARG +/− mice treated with benzo(a)pyrene by stabilizing the expression of Wnt ligand [95]. These observations make PARG a perfect target for cancer chemotherapy.…”

Poly(ADP-Ribose) Glycohydrolase (PARG) vs. Poly(ADP-Ribose) Polymerase (PARP) – Function in Genome Maintenance and Relevance of Inhibitors for Anti-cancer Therapy

“…The mechanisms by which changes in PARP expression can induce tumor formation and progression are well documented (reviewed in Schiewer and Knudsen, 2014 ). However, it is far less clear the role PARG plays having been reported to both promote ( Dai et al, 2019 ; Marques et al, 2019 ) and suppress ( Molloy-Simard et al, 2012 ) tumourigenesis. Genetic manipulation of PARG has demonstrated roles in proliferation ( Pan et al, 2012 ), differentiation ( Wang et al, 2019 ), metastasis ( Li et al, 2012 ; Pan et al, 2012 ; Marques et al, 2019 ) and angiogenesis ( Pan et al, 2012 ).…”