Abstract 1484: Identification of the critical active enhancer and regulated transcripts contributing to the refractory nature of pancreatic cancer
Authors: Abe Tadashi , Saito Hideyuki , Nakano Yusuke , Hashimoto Masahiro , Ando Yuki , Hisamatsu Yuichi , Toshima Takeo , Yonemura Yusuke , Masuda Takaaki , Eto Ken , Ikegami Toru , Mimori Koshi 
Published: June 2023

Background: Pancreatic adenocarcinoma (PAAD) is the most lethal human cancer, with a 5-year survival rate of less than 10%. Thus, the identification of prognostic biomarkers as well as molecular therapeutic targets should be critical. Gene expression is regulated by various factors such as transcription factors, promoters, enhancers, DNA methylation, microRNAs, etc. Among them, it has been reported that enhancers play an essential role in the development and progression of cancer. This study aims to identify the novel regulatory element of gene transcription and therapeutic targets in pancreatic cancer by analyzing enhancers.

Material and Methods: We implemented NET-CAGE analysis to identify the active enhancer regions in pancreatic cancer cell lines and two immortalized normal pancreatic cell lines. As for the enhancer sequences, we conducted a motif analysis using an analytical pipeline, HOMER to capture sequence motifs enriched in the enhancers. The p-values output by HOMER were applied to identify transcription factor motifs enriched in the tumor cell lines compared to the normal cell lines. We analyzed RNA-sequencing data derived not only from 105 cases of in-house pancreatic cancer but from 178 cases of The Cancer Genome Atlas.

Results: We found that the enrichment of KLF and ELF family transcription factors was observed in cancer cell lines compared to normal cell lines. ELF4 expression was significantly higher in tumor tissues than in normal tissues (Wilcoxon rank sum test, p&lt;0.05). In survival analysis, high ELF4 expression was significantly associated with poor prognosis (Kaplan-Meier method, Log-rank test, p&lt;0.05). Immunohistochemical staining showed ELF4 expression in the nuclei of PAAD cells, and GSEA showed a positive correlation between increased ELF4 expression and the cell cycle-related gene sets and PI3K/AKT/mTOR-related gene sets.

Conclusions: The current result of the NET-CAGE enhancer analysis revealed that the KLF and ELF families might contribute to activating pancreatic cancer. As we know that KLF4 induces the pluripotency of somatic cells, KLF and ELF are considered to be cancer stemness-related genes. We are focusing on deciphering the regulatory element of the KLF and ELF to orchestrate downstream molecules of cancer stemness-related genes, which will lead to the intractability of pancreatic cancer.

Citation Format: Tadashi Abe, Hideyuki Saito, Yusuke Nakano, Masahiro Hashimoto, Yuki Ando, Yuichi Hisamatsu, Takeo Toshima, Yusuke Yonemura, Takaaki Masuda, Ken Eto, Toru Ikegami, Koshi Mimori. Identification of the critical active enhancer and regulated transcripts contributing to the refractory nature of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1484.