Abstract
The chromatin-binding DEK protein was recently reported to promote the growth of HPV+ and HPV- head and neck squamous cell carcinomas (HNSCCs). Relevant cellular and molecular mechanism(s) controlled by DEK in HNSCC remain poorly understood. While DEK is known to regulate specific transcriptional targets, global DEK-dependent gene networks in HNSCC are unknown. To identify DEK transcriptional signatures we performed RNA-Sequencing (RNA-Seq) in HNSCC cell lines that were either proficient or deficient for DEK. Bioinformatic analyses and subsequent validation revealed that IRAK1, a regulator of inflammatory signaling, and IRAK1-dependent regulatory networks were significantly repressed upon DEK knockdown in HNSCC. According to TCGA data, 14% of HNSCC specimens overexpressed IRAK1, thus supporting possible oncogenic functions. Furthermore, genetic or pharmacologic inhibition of IRAK1 in HNSCC cell lines was sufficient to attenuate downstream signaling such as ERK1/2 and to induce HNSCC cell death by apoptosis. Finally, targeting DEK and IRAK1 simultaneously enhanced cell death as compared to targeting either alone. Our findings reveal that IRAK1 promotes cell survival and is an attractive therapeutic target in HNSCC cells. Thus, we propose a model wherein IRAK1 stimulates tumor signaling and phenotypes both independently and in conjunction with DEK.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is a disease comprised of two distinct entities: human papillomavirus (HPV) positive and HPV negative
In order to define the consequences of DEK loss and identify DEK-dependent transcriptional networks in HNSCC cells, we used a well-established lentiviral approach that was previously published in this model system [8]
DEK down-regulation was connected to many genes of interest, including TNFAIP3, IL6, and MAPKs. Because these genes are well established for their downstream contributions to inflammation and immune signaling, we focused on the most important upstream transducer of toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling that was repressed following DEK loss, IRAK1
Summary
Head and neck squamous cell carcinoma (HNSCC) is a disease comprised of two distinct entities: human papillomavirus (HPV) positive and HPV negative. HPV− disease is attributable to tobacco and alcohol use, and its declining incidence in the US has been ascribed to the well-publicized health risks of these activities. HPV+ disease is on the rise, in younger patient populations [1]. While improved response to traditional chemotherapies and favorable long-term survival is observed in HPV+ patients, prognoses remain grim for patients with advanced and metastatic tumors [2]. Major quality of life issues arise due to treatment-related tissue damage [3]. The need for novel therapeutic targets and biomarkers for both HNSCC subsets must not be underestimated
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