Abstract LB-A26: Regulation of super-enhancers by GZ17-6.02 has therapeutic effect in pancreatic cancer (PDAC)

Abstract

Abstract Super enhancers (SE) are defined as unique areas of the genome that are densely bound by numerous transcription factors and play a pivotal role in the cell, including, tissue specification, identity and maintenance. Super enhancers are known to regulate the expression of associated genes and often drive high-level transcription. Studies have established many genes that play an important role in cancer biology as SE-driven oncogenes. It is likely that the peculiar pancreatic-specific tumor phenotype is a consequence of oncogenes hacking the resident tissue regenerative program, thus interfering with super enhancer-driven repair networks exerting a disproportionately disruptive effect on tumor versus normal pancreatic tissue. In this study, we have used ChIP-seq, RNA-seq and bioinformatics analysis to identify super-enhancers in the human metastatic pancreatic cancer cell line S2-007. H3K27ac marks were identified at enhancer region of numerous genes that act as SE in PDAC. The most prominent super-enhancers identified, based on a high level of H3K27ac marks were associated with c-MYC, MED1, OCT-4, NANOG and SOX2 genes. Previously we showed that “isovanillin”, one of the major compound of A. palaestinum, in combination with other anticancer agents termed as ‘GZ17-6.02’ inhibited tumor progression and metastasis in PDAC by suppressing cancer stem cells (CSCs) and sonic hedgehog (SHH) pathway in both in vitro and in vivo systems. In this study, we found that GZ17-6.02 affects acetylation of histones at some of the major SE related genes and at a high dose, a complete reduction in acetylation marks was seen in embryonic stem cell transcription factors. The mRNA sequencing data after GZ17-6.02 treatment also shows a reduction in transcription of, major transcription factors, SHH pathway genes, and stem cell markers. Cancer cells are more sensitive to lower doses of GZ17-6.02 than normal cells; hence normal cells are expected to have fewer side effects. There is no systematic study showing an association of super-enhancers with pancreatic cancer so far. Hence, in the present study, we have established that several super-enhancer targets can be targeted by GZ17-6.02 in PDAC. This study concludes that super-enhancers can be an important therapeutic target for PDAC. Citation Format: Chandrayee Ghosh, Sumedha Gunewardena, Santanu Paul, Cameron West, Animesh Dhar. Regulation of super-enhancers by GZ17-6.02 has therapeutic effect in pancreatic cancer (PDAC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A26.