title: ETS family transcriptional regulators drive chromatin dynamics and malignancy in squamous cell carcinomas.
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.
authors.affiliation: Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, United States.
authors.forename: Hanseul
authors.initials: H
authors.lastname: Yang
authors.affiliation: Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schramek
authors.affiliation: Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, United States.
authors.forename: Rene C
authors.initials: RC
authors.lastname: Adam
authors.affiliation: Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, United States.
authors.forename: Brice E
authors.initials: BE
authors.lastname: Keyes
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, New York, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, New York, United States.|Departments of Genetics and Neuroscience, Albert Einstein College of Medicine, New York, United States.
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, United States.
authors.forename: Elaine
authors.initials: E
authors.lastname: Fuchs
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism*; D044127:Epigenesis, Genetic; D053263:Gene Regulatory Networks; D006801:Humans
chemical_list: D002843:Chromatin
keywords: ETS family transcription factors; Super-enhancer profiling; developmental biology; mouse; skin squamous cell carcinomas; stem cells