Abstract 1398: Super-enhancers: Possible target in pancreatic cancer for therapeutic approaches
Authors: Ghosh Chandrayee , Gunewardena Sumedha , Dandawate Prasad , Paul Santanu , Tawfik Ossama , West Cameron , Anant Shrikant , Dhar Animesh 
Published: August 2018

Introduction: Super enhancers (SE) are distinctive areas of the genome that are densely bound by numerous transcription factors and play a pivotal role in the cell identity, tissue specification, and maintenance. Although the exact functions of super-enhancers are not yet well understood, these regions are known for driving high-level transcription. Studies have established most of the oncogenes playing important role in cancer are driven by SEs. 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 might exert a disproportionately disruptive effect on tumor versus normal pancreatic tissue.

The hypothesis of this study is that the tumor cells in PDAC acquire super-enhancers at key oncogenes during tumor development, which drive higher levels of transcription of these genes than in healthy cells. Acquired super-enhancers may thus be biomarkers that could be useful for diagnosis and therapeutic intervention. Thus drugs which could affect super enhancers in cancer may have therapeutic effect.

Methods: In this study, we have used ChIP-Seq techniques and bioinformatics analysis following qPCR to identify SE in PDAC cell lines and in pancreatic cancer tissues. Immunohistochemistry, proliferation assays, western blot, RNAseq and CETSA (cellular thermal shift assay) have been performed for understanding the role of enhancers and SE in PDAC.

Results: 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. Differential association of SE in non-cancerous pancreatic cells, cancerous and metastatic cell lines of PDAC have been implicated in comparison normal and PDAC cells. In this study, we found that GZ17-6.02, combinations of natural compounds, affects acetylation of some of the major SE related genes and at a higher 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 both in vitro and in vivo pancreatic cancer orthotopic models. Cancer cells are more sensitive to lower doses of GZ17-6.02 than normal cell; hence normal cells are expected to have less side effects.

Conclusions: There is no systematic study showing an association of SE with pancreatic cancer so far. Hence, in the present study, we have established that several super-enhancer marks can be targeted by combination of natural compounds, 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, Prasad Dandawate, Santanu Paul, Ossama Tawfik, Cameron West, Shrikant Anant, Animesh Dhar. Super-enhancers: Possible target in pancreatic cancer for therapeutic approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1398.