title: IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival.
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.
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Allie K
authors.initials: AK
authors.lastname: Adams
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Lyndsey C
authors.initials: LC
authors.lastname: Bolanos
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Dexheimer
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Rebekah A
authors.initials: RA
authors.lastname: Karns
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Kakajan
authors.initials: K
authors.lastname: Komurov
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Anil G
authors.initials: AG
authors.lastname: Jegga
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Casper
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Yash J
authors.initials: YJ
authors.lastname: Patil
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Wilson
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Starczynowski
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Susanne I
authors.initials: SI
authors.lastname: Wells
mesh_terms: D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002470:Cell Survival / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D016133:Polymerase Chain Reaction; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C084738:DEK protein, human; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: DEK; HNSCC; HPV; IRAK1; RNA-Seq