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Reactivation of super-enhancers by KLF4 in human Head and Neck Squamous Cell Carcinoma

ABSTRACT: Head and Neck Squamous Cell Carcinoma (HNSCC) is a disease of significant morbidity and mortality ranked as the sixth leading cause of cancer worldwide rarely diagnosed in early stages. Despite extensive genetic research, development of therapeutics and diagnostic markers has been limited due to the extensive heterogeneity and complexity of the disease. Herein, we generated a comprehensive understanding of the transcriptional regulatory aberrations in HNSCC based on the epigenomic and transcriptomic study of the mesenchymal cell line SCC25. Our findings support a fundamental role for the transcription factor Krüppel-like Factor 4 (KLF4) in HNSCC, through its binding to differential active regulatory elements, the majority of which are super-enhancers, and the transcriptional upregulation of key HNSCC cancer genes. Upregulation of these targets often realizes with the concurrent action of TP63 or ERG. Approximately 70% of the activated targets bear a simultaneous loss of the H3K27me3 histone repressive mark and are confirmed EZH2 targets in healthy states, corroborating the tumor suppressor role of the Polycomb Repressive Complex 2 in head and neck cancers. Our current results lead us to propose a model where the upregulation and binding of KLF4 activates the HNSCC state, by re-activating repressed chromatin domains at key genes via super-enhancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103554 | GEO | 2019/09/06

REPOSITORIES: GEO

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