Glutathione S-transferasesP1 AA (105Ile) allele increases oral cancer risk, interacts strongly with c-Jun Kinase and weakly detoxifies areca-nut metabolites

Pallavi Yadav,Puja Chatterjee,Nabamita Boruah,Souvik Mukherjee,Anupam Chatterjee,Henry B. Nongrum,Chongtham Sovachandra Singh,Atanu Bhattacharjee,Hughbert Dakhar,Atanu Banerjee

doi:10.1038/s41598-020-63034-3

Abstract

The Glutathione S-transferases (GSTs) protects cellular DNA against oxidative damage. The role of GSTP1 polymorphism (A313G; Ile105Val) as a susceptibility factor in oral cancer was evaluated in a hospital-based case-control study in North-East India, because the habit of chewing raw areca-nut (RAN) with/without tobacco is common in this region. Genetic polymorphism was investigated by genotyping 445 cases and 444 controls. Individuals with the GSTP1 AA-genotype showed association with the oral cancer (OR = 3.1, 95% CI = 2.4–4.2, p = 0.0002). Even after adjusting for age, sex and habit the AA-genotype is found to be significantly associated with oral cancer (OR = 2.4, 95% CI = 1.7–3.2, p = 0.0001). A protein-protein docking analysis demonstrated that in the GG-genotype the binding geometry between c-Jun Kinase and GSTP1 was disrupted. It was validated by immunohistochemistry in human samples, showing lower c-Jun-phosphorylation and down-regulation of pro-apoptotic genes in normal oral epithelial cells with the AA-genotype. In silico docking revealed that AA-genotype weakly detoxifies the RAN/tobacco metabolites. In addition, experiments revealed a higher level of 8-Oxo-2′-deoxyguanosine induction in tumor samples with the AA-genotype. Thus, habit of using RAN/tobacco and GSTP1 AA-genotype together play a significant role in predisposition to oral cancer risk by showing higher DNA-lesions and lower c-Jun phosphorylation that may inhibit apoptosis.

Highlights

The oral squamous cell carcinoma (OSCC) is the most common cancer in India, with highest occurrence in the north-eastern part of the country[1]
It has been demonstrated in Assam and other regions in North-East India that GSTM1 null genotype is associated with esophageal cancer in fermented areca-nut chewers whereas smoking and alcohol do not show any association either with this or GSTT1 genotypes[14]
We have explored the association of GSTP1 (A313G) with the risk of oral cancer in the people chewing raw areca-nut (RAN) with and without tobacco

Summary

Introduction

The oral squamous cell carcinoma (OSCC) is the most common cancer in India, with highest occurrence in the north-eastern part of the country[1]. The human cytosolic GST family, comprising 16 genes belonging to 8 distinct classes, is well studied and considered to be relevant to various disease manifestations[12,13] It has been demonstrated in Assam and other regions in North-East India that GSTM1 null genotype is associated with esophageal cancer in fermented areca-nut chewers whereas smoking and alcohol do not show any association either with this or GSTT1 genotypes[14]. GSTP1 plays an important role in modulating activities of other enzymes through protein-protein interactions. It is an inhibitor of c-Jun N-terminal kinase (JNK) whose activation leads to c-Jun phosphorylation[25]. GSTP1-mediated JNK inhibition occurs in a dose-dependent manner with up to 80% inhibition of its c-Jun kinase activity has been reported in mouse fibroblast cell line[26]

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