Super-Enhancer-Driven Transcriptional Dependencies in Cancer

Sengupta, Satyaki; George, Rani E.

doi:10.1016/j.trecan.2017.03.006

Cited by 252 publications

(215 citation statements)

References 88 publications

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“…Previously, a combination approach using a BET protein inhibitor and a histone deacetylase inhibitor led to near-complete tumor regression and improved animal survival in a PDA GEMM [28]. Super-enhancer activation has recently been shown to be fundamental in the pathophysiology of a variety of neoplasms [38] and is intimately associated with Hmg2a in PDA, as super-enhancer attenuation has been demonstrated to downregulate Hmg2a expression and the growth of PDA cells in a three-dimensional in vitro model [39]. Our study is the first to demonstrate that these epigenetic regulatory mechanisms in PDA are present in specific tissue compartments, namely mesenchymal cancer cells and CAFs.…”

Section: Discussionmentioning

confidence: 99%

Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution

Hosein

Huang

Wang

et al. 2019

Preprint

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Background & AimsPancreatic ductal adenocarcinoma (PDA) is a major cause of cancer-related death with limited therapeutic options available. This highlights the need for improved understanding of the biology of PDA progression. The progression of PDA is a highly complex and dynamic process featuring changes in cancer cells and stromal cells; however, a comprehensive characterization of PDA cancer cell and stromal cell heterogeneity during disease progression is lacking. In this study, we aimed to profile cell populations and understand their phenotypic changes during PDA progression.MethodsWe employed single-cell RNA sequencing technology to agnostically profile cell heterogeneity during different stages of PDA progression in genetically engineered mouse models.ResultsOur data indicate that an epithelial-to-mesenchymal transition of cancer cells accompanies tumor progression. We also found distinct populations of macrophages with increasing inflammatory features during PDA progression. In addition, we noted the existence of three distinct molecular subtypes of fibroblasts in the normal mouse pancreas, which ultimately gave rise to two distinct populations of fibroblasts in advanced PDA, supporting recent reports on intratumoral fibroblast heterogeneity. Our data also suggest that cancer cells and fibroblasts are dynamically regulated by epigenetic mechanisms.ConclusionThis study systematically outlines the landscape of cellular heterogeneity during the progression of PDA. It strongly improves our understanding of the PDA biology and has the potential to aid in the development of therapeutic strategies against specific cell populations of the disease.

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Section: Discussionmentioning

confidence: 99%

Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution

Hosein

Huang

Wang

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Super‐enhancer and its associated genes are frequently located within a loop connected by two CTCF sites co‐occupied by cohesion within TADs, as an example, 84% of super‐enhancers and 48% of typical enhancers are located within such structures in mESCs, respectively . Remarkably, super‐enhancers are capable of maintaining cell identity, determining cell fate, driving oncogene transcription in cancer cells …”

Section: Super‐enhancer Determines Cell Indentity and Fatementioning

confidence: 99%

“…Super‐enhancers have been found to drive the expression of a few critical oncogenes in several types of tumor cells . In Nasopharyngeal carcinoma , super‐enhancers are linked to genes important for oncogenesis including ETV6 .…”

Section: Super‐enhancer Determines Cell Indentity and Fatementioning

confidence: 99%

“…In contrast, duplication of super‐enhancers leads to overexpression of a key oncogenic transcription factor, which then activates other cancer‐related genes in squamous cell carcinomas . Super‐enhancers can be targeted through inhibition of chromatin and transcriptional regulators that disproportionately bound to these regulatory elements super‐enhancers . Recent studies have demonstrated that JQ1 (a competitive inhibitor of BRD4, and a covalent inhibitor of CDKs), selectively kill cancer cells by inhibiting SE‐driven oncogenic transcription, with both agents lacking systemic toxic effects in vivo …”

Section: Super‐enhancer Determines Cell Indentity and Fatementioning

confidence: 99%

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Enhancer and super‐enhancer: Positive regulators in gene transcription

Peng

Zhang

2018

Anim Models and Exp Med

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Enhancer is a positive regulator for spatiotemporal development in eukaryotes. As a cluster, super‐enhancer is closely related to cell identity‐ and fate‐determined processes. Both of them function tightly depending on their targeted transcription factors, cofactors, and genes through distal genomic interactions. They have been recognized as critical components and played positive roles in transcriptional regulatory network or factory. Recent advances of next‐generation sequencing have dramatically expanded our ability and knowledge to interrogate the molecular mechanism of enhancer and super‐enhancer for transcription. Here, we review the history, importance, advances and challenges on enhancer and super‐enhancer field. This will benefit our understanding of their function mechanism for transcription underlying precise gene expression.

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“…Epigenetic alterations leading to aberrant transcription have been increasingly recognized in carcinogenesis ever since the emergence of the concept of the super-enhancer. These unique enhancer regions play a central role in the maintenance of cancer cell identity and drive oncogenic transcriptional programs to which cancer cells are highly addicted (Whyte et al, 2013;Lovén et al, 2013;Sengupta & George, 2017). Enhancer reprogramming, which is caused by the redistribution of transcription factors and the subsequent changes in transcription factor networks, drives cancer cell phenotypic drift during cancer initiation and progression Denny et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Enhancer Remodeling Promotes Tumor-Initiating Activity in NRF2-Activated Non-Small Cell Lung Cancers

Okazaki

Anzawa

Liu

et al. 2020

Preprint

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Transcriptional dysregulation, which can be caused by genetic and epigenetic alterations, is a fundamental feature of many cancers. A key cytoprotective transcriptional activator, NRF2, is often aberrantly activated in non-small cell lung cancers (NSCLCs) and supports both aggressive tumorigenesis and therapeutic resistance. Herein, we found that persistently activated NRF2 in NSCLCs generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. Elevated accumulation of CEBPB in NRF2-activated NSCLCs was found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which NOTCH3 enhancer was shown to be critical for the promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes tumor-initiating activity and drives malignancy of NRF2-activated NSCLCs via establishment of the NRF2-NOTCH3 regulatory axis.

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Super-Enhancer-Driven Transcriptional Dependencies in Cancer

Cited by 252 publications

References 88 publications

Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution

Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution

Enhancer and super‐enhancer: Positive regulators in gene transcription

Enhancer Remodeling Promotes Tumor-Initiating Activity in NRF2-Activated Non-Small Cell Lung Cancers

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