Oncotarget

Research Papers:

Super-enhancers: novel target for pancreatic ductal adenocarcinoma

Chandrayee Ghosh, Santanu Paul, Prasad Dandawate, Sumedha S. Gunewardena, Dharmalingam Subramaniam, Cameron West, Shrikant Anant and Animesh Dhar _

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Oncotarget. 2019; 10:1554-1571. https://doi.org/10.18632/oncotarget.26704

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Abstract

Chandrayee Ghosh1, Santanu Paul1, Prasad Dandawate1, Sumedha S. Gunewardena2, Dharmalingam Subramaniam1, Cameron West3, Shrikant Anant1,2 and Animesh Dhar1,2

1Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS-66160, USA

2Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS-66160, USA

3Genzada 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.


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