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

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Abstract

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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Hanseul Yang

Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

Competing interests
No competing interests declared.
Daniel Schramek

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, United States

Competing interests
No competing interests declared.
Rene C Adam

Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

Competing interests
No competing interests declared.
Brice E Keyes

Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

Competing interests
No competing interests declared.
Ping Wang

Department of Neurology, Albert Einstein College of Medicine, New York, United States

Competing interests
No competing interests declared.
Deyou Zheng

Department of Neurology, Albert Einstein College of Medicine, New York, United States

Competing interests
No competing interests declared.
Elaine Fuchs

Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

For correspondence
elaine.fuchs@rockefeller.edu

Competing interests
Elaine Fuchs, Reviewing editor, eLife.

Ethics

Animal experimentation: Mice were maintained in the Association for Assessment and Accreditation of Laboratory Animal Care-accredited animal facility of The Rockefeller University (RU), and procedures were performed with Institutional Animal Care and Use Committee (IACUC)-approved protocols (#13622-H, #14693-H and #14765-H).

Human subjects: Tissue microarrays comprising healthy human skin samples, human skin SCCs as well as head and neck SCCs (HNSCC) were obtained from US Biomax, Rockeville. All tissue is collected under the highest ethical standards with the donor being informed completely and with their consent. The company followed standard medical care and protect the donors' privacy. All human tissues are collected under HIPPA approved protocols.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.