Abstract 2431: Identification of the underlining relationship of bivalent histone modifications with pancreatic cancer stem cells by bioinformatic analysis

Abstract

Abstract Epigenetic alterations are known to involve in cancer stem cells (CSCs) reprogramming. CSCs have been reported to be more resistant to anti-tumor treatments than the non-stem cancer cells, suggesting that surviving CSCs could be responsible for tumor relapse after therapy. The most relevant epigenetic alteration, histone modification has been shown in recent scientific studies to contribute to the regulation of cancer stem cell features in tumor metastasis, progression and response to chemotherapy. The pre-transcriptional regulator, bivalent histone modifications were reported to be involved in the development of CSCs recently. The synchronous presence of functionally opposite histone marks at transcript start sequence (TSS) is known as “Bivalency”. The H3K4me3 as well as H3K27me3, the prominent histone methylations of bivalency, are concerned in transcriptional activation and transcriptional repression respectively. The balance between H3K4me3 and H3K27me3 results in diverse chromatin architectures, ensuing in different transcription states of downstream genes: “poised”, “activated” or “repressed”. The current study is aimed to explore the relationship of bivalent histone modifications, (upregulation or expression of H3K4me3, and down-regulation or repression H3K27me3) the epigenetic regulations with the expression of pancreatic cancer stem cells (CD44, CD24, CD133, Ep-CAM, ALDH1A3) in pancreatic cancer. Protein expression profiles were analyzed using biological informatics methods (string database; Cytoscape database, BioGrid, Reactome, MatrixDB, NCBI Gene and NCBI epigenomics metadata analyses) to identify the relationship of bivalent histone modifications with expressed genes of pancreatic cancer stem cells (CD44, CD24, CD133, Ep-CAM, ALDH1A3). NCBI Biosystems database showed that 197 genes are involved in the Integrated Pancreatic Cancer Pathway model using KEGG database, but the relationship of bivalent histone modifications with the expression of pancreatic cancer stem cells (CD44, CD24, CD133, Ep-CAM, ALDH1A3) in pancreatic cancer has not been showed earlier. Our analysis showed the protein-protein interaction (PPI) network was constructed for such a relationship of closely related 45 significant genes. Among these 45 genes, a total of 7 pancreatic cancer stem cell markers (CSCs) was closely associated with upregulation or expression of H3K4me3, and down-regulation or repression H3K27me3 through EZH2 and PHF19 with a high degree of interaction in the PPI network. We are also able to analyze the role of H3K27ac in regulating target genes in 18 samples of pancreatic cancer cell lines using the ChIP-sequences data set of study SRA 109996 from NCBI NLM Sequence Read Archive from Run Browser Accession number ERR2708462. Therefore, this study identified the significant relationship of bivalent histone modifications associated with pancreatic CSCs which may be the novel biomarkers and target candidates in designing drugs against pancreatic cancer. This work was part of the honors option project (HOP) of Natalia Ortega mentored by Dr. Jayanta K. Das, at MDC north campus. Citation Format: Natalia Ortega, Madhumita Das, Marco A. Ruiz, Jairo Ramos, Jayanta Kumar Das. Identification of the underlining relationship of bivalent histone modifications with pancreatic cancer stem cells by bioinformatic analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2431.