ETS family transcriptional regulators drive chromatin dynamics and malignancy in squamous cell carcinomas

Tumor-initiating stem cells (SCs) exhibit distinct patterns of transcription factors and gene expression compared to healthy counterparts. Here, we show that dramatic shifts in large open-chromatin domain (super-enhancer) landscapes underlie these differences and reflect tumor microenvironment. By i...

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Published ineLife Vol. 4; p. e10870
Main Authors Yang, Hanseul, Schramek, Daniel, Adam, Rene C, Keyes, Brice E, Wang, Ping, Zheng, Deyou, Fuchs, Elaine
Format Journal Article
LanguageEnglish
Published England eLife Science Publications, Ltd 21.11.2015
eLife Sciences Publications Ltd
eLife Sciences Publications, Ltd
Subjects
Carcinoma, Squamous Cell - pathology
Cell Proliferation
Chromatin
Chromatin - metabolism
Comparative analysis
Development and progression
Developmental Biology and Stem Cells
DNA binding proteins
Epigenesis, Genetic
Epigenetic inheritance
ETS family transcription factors
Gene mutations
Gene Regulatory Networks
Genes
Genetic aspects
Genetic research
Genetic transcription
Humans
Skin cancer
skin squamous cell carcinomas
Squamous cell carcinoma
Stem cells
Super-enhancer profiling
ETS family transcription factors
mouse
stem cells
skin squamous cell carcinomas
developmental biology
Super-enhancer profiling
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Summary:Tumor-initiating stem cells (SCs) exhibit distinct patterns of transcription factors and gene expression compared to healthy counterparts. Here, we show that dramatic shifts in large open-chromatin domain (super-enhancer) landscapes underlie these differences and reflect tumor microenvironment. By in vivo super-enhancer and transcriptional profiling, we uncover a dynamic cancer-specific epigenetic network selectively enriched for binding motifs of a transcription factor cohort expressed in squamous cell carcinoma SCs (SCC-SCs). Many of their genes, including Ets2 and Elk3, are themselves regulated by SCC-SC super-enhancers suggesting a cooperative feed-forward loop. Malignant progression requires these genes, whose knockdown severely impairs tumor growth and prohibits progression from benign papillomas to SCCs. ETS2-deficiency disrupts the SCC-SC super-enhancer landscape and downstream cancer genes while ETS2-overactivation in epidermal-SCs induces hyperproliferation and SCC super-enhancer-associated genes Fos, Junb and Klf5. Together, our findings unearth an essential regulatory network required for the SCC-SC chromatin landscape and unveil its importance in malignant progression.
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Department of Molecular Genetics, University of Toronto, Ontario, United States.
These authors contributed equally to this work.
The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Canada.
ISSN:2050-084X
2050-084X
DOI:10.7554/elife.10870