Evaluation of epigenetic profile associated with DNA repair systems induced by Helicobacter pylori

Although thousands of DNA damaging events occur in each cell every day, efficient DNA repair pathways have evolved to counteract them. The DNA repair machinery plays a key role in maintaining genomic stability by avoiding the maintenance of mutations. The DNA repair enzymes continuously monitor the DNA to correct any damage that is caused by exogenous and endogenous mutagens. In addition to mutations, which can be either inherited or somatically acquired, epigenetic changes in DNA repair genes has been associated with carcinogenesis. Gastric cancer (GC) represents the second highest cause of cancer mortality worldwide. The disease develops from the accumulation of several genetic and epigenetic changes during the lifetime. Among the risk factors, "Helicobacter pylori" ("H. pylori") infection is considered the main driving factor to gastric cancer development. This bacteria induces the loss of key features of epithelial differentiation, the transition to a mesenchymal phenotype, endorses the transformation of gastric stem cells and therefore tumor formation. These cells with self-renewal properties (called cancer stem cells, CSCs) are also resistant to GC therapy and subsequently responsible for tumor recurrence and metastasis. Therefore, the determination of the mechanisms of CSCs regulation and maintenance are essential for understanding the pathobiology of GC. Thus, the current study analyzed the role of "H. pylori" infection on the epigenetic regulation of DSB and BER DNA repair systems in epithelial and CSCs. In this work we have identified that H. pylori infection stimulates key features of the development of cancer, such as cell proliferation, nuclear translocation of 'beta'-catenin, DNA damage and consequent induction of DNA repair genes response in a virulence factors dependent manner. In addition, it was determined that the induction of DNA repair is mediated by H3 and H4 hyperacetylation and hypomethylation of promoter region of certain genes. it was determined that SOX9 is essential for maintenance of CSCs and stimulate gastric key processes such as tumor cell proliferation, nuclear translocation 'beta'-catenin, chemoresistance, decreased apoptosis and senescence. In addition, we found a regulatory interaction loop between SOX9 and 'beta'-catenin. Interestingly, it was demonstrated that SOX9 is induced in response to "H. pylori" both in gastric epithelial cells as CSCs. Finally, it was observed that CSCs are regulated by ATM and there is an ATM increase in CSCs in response to H. pylori. From these results, we concluded that the DNA repair induction occurs in response to "H. pylori" to prevent or reduce chromosome aberrations. Our findings provide novel epigenetic mechanism associated to DNA damage caused by "H. pylori" infection (AU)