Super-enhancers: novel target for pancreatic ductal adenocarcinoma

// Chandrayee Ghosh 1 , Santanu Paul 1 , Prasad Dandawate 1 , Sumedha S. Gunewardena 2 , Dharmalingam Subramaniam 1 , Cameron West 3 , Shrikant Anant 1, 2 and Animesh Dhar 1, 2 1 Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS-66160, USA 2 Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS-66160, USA 3 Genzada Pharmaceuticals, Sterling, KS-67579, USA Correspondence to: Animesh Dhar, email: adhar@kumc.edu Keywords: PDAC; super-enhancers; therapeutics; ChIP-Seq; cancer stem cells Received: December 12, 2018      Accepted: February 01, 2019      Published: February 22, 2019 ABSTRACT Super-enhancers (SEs) are unique areas of the genome which drive high-level of transcription and play a pivotal role in the cell physiology. Previous studies have established several important genes in cancer as SE-driven oncogenes. It is likely that oncogenes may hack the resident tissue regenerative program and interfere with SE-driven repair networks, leading to the specific pancreatic ductal adenocarcinoma (PDAC) phenotype. Here, we used ChIP-Seq to identify the presence of SE in PDAC cell lines. Differential H3K27AC marks were identified at enhancer regions of genes including c-MYC, MED1, OCT-4, NANOG, and SOX2 that can act as SE in non-cancerous, cancerous and metastatic PDAC cell lines. GZ17-6.02 affects acetylation of the genes, reduces transcription of major transcription factors, sonic hedgehog pathway proteins, and stem cell markers. In accordance with the decrease in Oct-4 expression, ChIP-Seq revealed a significant decrease in the occupancy of OCT-4 in the entire genome after GZ17-6.02 treatment suggesting the possible inhibitory effect of GZ17-6.02 on PDAC. Hence, SE genes are associated with PDAC and targeting their regulation with GZ17-6.02 offers a novel approach for treatment.