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

• Published in: Scientific reports Vol. 10; no. 1; p. 6032
• Main Authors: Yadav, Pallavi, Banerjee, Atanu, Boruah, Nabamita, Singh, Chongtham Sovachandra, Chatterjee, Puja, Mukherjee, Souvik, Dakhar, Hughbert, Nongrum, Henry B., Bhattacharjee, Atanu, Chatterjee, Anupam
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.04.2020; Nature Publishing Group
• Subjects: 38; 38/77; 631/114; 631/67/68; Adult; Aged; Aged, 80 and over; Alleles; Apoptosis; Areca - metabolism; c-Jun protein; Chewing; Crystallography, X-Ray; Deoxyguanosine; Deoxyribonucleic acid; DNA; DNA Damage; Epithelial cells; Female; Gene polymorphism; Gene regulation; Genetic Predisposition to Disease; Genotype & phenotype; Genotyping; Glutathione S-Transferase pi - chemistry; Glutathione S-Transferase pi - genetics; Glutathione S-Transferase pi - metabolism; Glutathione transferase; Health risk assessment; Humanities and Social Sciences; Humans; Immunohistochemistry; JNK Mitogen-Activated Protein Kinases - metabolism; Male; Metabolites; Middle Aged; Models, Molecular; Mouth Neoplasms - etiology; Mouth Neoplasms - genetics; Mouth Neoplasms - metabolism; multidisciplinary; Nuts; Oral cancer; Oxidative Stress; Phosphorylation; Polymorphism; Polymorphism, Single Nucleotide; Science; Science (multidisciplinary); Tobacco; Tobacco Use - adverse effects; Tobacco Use - metabolism; Transcription factors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-63034-3

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.