Expression Status Of H3K27 Acetylation And Its Roles In Different Gene’s Expressions In Pancreatic Cancer

Background:The pancreas is an organ located in the abdomen.It is responsible for turning the food we consume into energy for the body’s cells.Correspondingly,the pancreas has two primary functions:an exocrine involvement in digestion and an endocrine role in blood sugar regulation.Pancreatitis and pancreatic cancer are two major diseases that affect the pancreas The symptoms of pancreatic cancer are not apparent,and the disease progresses too quickly However,there are no precise biomarkers for early detection or successful clinical screening tools for this cancer.Pancreatic cancer development is a dynamic biochemical pathway involving many forms of genetic alteration.Subsequently,Pancreatic cancer is a malignant disorder that is referred to as the world’s fourth-worst malignancy.Evidently,according to statistics,about 45.000 new cases are expected to be reported in the United States per year,with a 5-year mortality rate of less than 5%.According to many reports,histone tail alterations have been found in some cancer,including pancreatic cancer.More,over anomalies like these play a significant role in cancers like the one mentioned above.All of these marks are used to mutate large tumor suppressors,including p16 and p53,and disrupt genomic integrity,all of which contribute to pancreatic cancer development and progressionMost histone-modifying enzymes work on one or a few histone marks,whether to enhance or remove the histone tail or recognize a new alteration.Epigenetic modifications are inherited gene expression alterations that do not alter the DNA pattern.Centered on non-DNA sequences retrieved through cell division,these variations are indicated to be heritable.All significant epigenetic regulation mechanisms include DNA methylation,histone modifications,chromatin remodeling,and non-coding ribonucleic acids.These changes will change chromatin’s composition to make it more useful,resulting in gene expression.According to research,epigenetic changes in cancer cells are often linked to tumor growth,development,and metastasis.Different histone variants’ activation and decay have been related to a poor prognosis in other cancer forms.While much progress has been made on individual genes and proteins,many aspects of the pancreatic cancer process,such as histone modifications,especially H3K27ac,remain unknown.Therefore,this research aims to establish the status of the expression of H3K27ac and the genes associated with its expression in pancreatic cancer by using two mouse models of pancreatic cancerMethods:In this study,we used Immunohistochemistry to assess the expression levels of H3K27ac in pancreatic cancer tissues from the Wild Type and K-rasLSL.G12D/+;Trp53R172H/+;Pdx-l-Cre mouse models.Surely,ChIP-Seq and its related statistics analysis were used to track H3K27 ac occupancy in the tissues.Furthermore,the R package named ClusterProfiler was used to determine GO terms.Consequently,HOMER/4.8 was used to identify transcription factors related to the high levels of H3K27ac.TCGA Data has been used to assess the genes’ expression levels associated with the H3K27ac occupancy and their overall survival analysis.Lastly,RNA extraction was performed From WT(normal)and KPC(cancer)tissues;the QT-PCR followed.This was used to validate the genes’ expression levels.Results:This study found that the H3K27ac level is high in K-rasLSL.G12D/+;Trp53R172H/+;Pdx-1-Cre tissues compared to WT(normal)tissues.For this reason,the results mentioned above prompted us to assess the H3K27 acetylation occupancy in both Wild type and K-rasLSL.G12D/+;Trp53R172H/+;Pdx-1-Cre(KPC)tissues;by performing ChIP-Seq analysis,we noted that H3K27 acetylation is high in the GAIN compartment,and we also found that there were many genes expressed related to the high level of H3K27ac in the GAIN compartment.Certainly,the Ras protein pathway regulation was among the most enriched GO term identified in this study.Abnormal RAS protein upregulation is reported to be correlated with numerous major pancreatic cancer events,such as accelerated proliferation,suppression of apoptosis,altered metabolism,shifts in the tumor’s microenvironment,elimination of immune response,and metastases.Moreover,we identified 11 motifs related to the increased levels of H3K27ac in K-rasLSL.G12D/+;Trp53R172H/+;Pdx-1-Cre mouse model tissues.In those 11 identified genes,we found 5 genes(GATA6,NF1,SAMAD4,TCF12,and TRSP1)having high H3K27ac occupancy in KPC compared to WT tissues.Having identified the above genes,we verified the expression levels of those five genes in independent datasets,which confirmed that those genes are high in cancer than normal tissues in pancreatic cancer;we validated that those genes are also high in K-rasLSL.G12D/+;Trp53R172H/+;Pdx-1-Cre(cancer)Wild type(normal)during this study.Overall survival rates analysis of the five selected genes revealed that low TCF12 and TRSP1 have improved survival rates than other remaining genes.Conclusion:In conclusion,H3K27 acetylation levels are high in Tumor(KPC)tissues compared to normal tissues(WT),and H3K27ac high occupancy is significantly related to different gene expressions in pancreatic cancer.