GSE129182
H2A.Z overexpression suppresses senescence and chemosensitivity in pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma is one of the most intractable and devastating of all malignant tumors. Epigenetic modifications involving both DNA methylation and histone modification have a relationship between tumor initiation and progression. However, the contribution of histone variants in the PDAC is unknown. Here, we demonstrated that the histone variant H2A.Z is highly expressed in PDAC cell lines and PDAC patients and its overexpression correlated with poor prognosis. We found that the three-histone H2A.Z isoforms (H2A.Z.1, H2A.Z.2.1 and, H2A.Z.2.2), are highly expressed in PDAC cell lines and PDAC patients. Knockdown of three H2A.Z isoforms induces a senescent phenotype, cell cycle arrest in phase G2/M, increased cyclin-dependent kinase inhibitor CDKN2A/p16, SA-ß-galactosidase activity and interleukin 8 production in PDAC. Transcriptome analysis of knockdown of the H2A.Z isoforms showed altered gene expression in the fatty acid biosynthesis. As well as in the genes that control the cell cycle and DNA damage repair. Furthermore, H2A.Z isoform deficiency, reduces the tumor size in a mouse xenograft model in vivo, and sensitizes PDAC cells to gemcitabine. These results make H2A.Z a potential candidate as a diagnostic biomarker and therapeutic target for PDAC Overall design: mRNA profiles of PANC-1 pancreatic cancer cell line (WT) and PZT-2 (KD of three H2A.Z isoforms), using Illumina NextSeq 500