Abstract
Head and Neck Squamous Cell Carcinoma (HNSCC) is a heterogeneous disease of significant mortality and with limited treatment options. Recent genomic analysis of HNSCC tumors has identified several distinct molecular classes, of which the mesenchymal subtype is associated with Epithelial to Mesenchymal Transition (EMT) and shown to correlate with poor survival and drug resistance. Here, we utilize an integrated approach to characterize the molecular function of ETS1, an oncogenic transcription factor specifically enriched in Mesenchymal tumors. To identify the global ETS1 cistrome, we have performed integrated analysis of RNA-Seq, ChIP-Seq and epigenomic datasets in SCC25, a representative ETS1high mesenchymal HNSCC cell line. Our studies implicate ETS1 as a crucial regulator of broader oncogenic processes and specifically Mesenchymal phenotypes, such as EMT and cellular invasion. We found that ETS1 preferentially binds cancer specific regulator elements, in particular Super-Enhancers of key EMT genes, highlighting its role as a master regulator. Finally, we show evidence that ETS1 plays a crucial role in regulating the TGF-β pathway in Mesenchymal cell lines and in leading-edge cells in primary HNSCC tumors that are endowed with partial-EMT features. Collectively our study highlights ETS1 as a key regulator of TGF-β associated EMT and reveals new avenues for sub-type specific therapeutic intervention.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with an annual incidence of roughly 600,000 cases; 50,000 cases are diagnosed annually in the United States alone[1, 2]
E26 transformation-specific 1 (ETS1) function has been shown to be associated with a wide range of cellular responses that include increased proliferation, angiogenesis, metastasis and drug resistance
We focus on Head and Neck Squamous Cell Carcinoma (HNSCC) and discover that higher expression of ETS1 is more pronounced in the mesenchymal subtypes of HNSCC, which represent tumors with enriched expression of Epithelial to Mesenchymal Transition (EMT) markers and inflammation
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with an annual incidence of roughly 600,000 cases; 50,000 cases are diagnosed annually in the United States alone[1, 2]. The major etiologies of this cancer are related to tobacco and alcohol consumption as well as infection with human papillomavirus (HPV), which has emerged in the past two decades as a prominent risk factor leading to a substantial proportion of HNSCCs diagnosed each year[4,5,6,7,8]. Initial grouping of HNSCC patients based on the unsupervised clustering of global gene expression revealed four major subtypes that were designated as Basal, Mesenchymal, Classical and Atypical[17, 18]. It is becoming clear that each subtype of HNSCC possess a distinct pattern of gene expression that sets it apart in terms of the underlying biology, key drivers and potentially actionable targets
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