The proposed work builds on the previously funded research project entitled """"""""Role and regulation of the human DEK oncogene."""""""" The original application was focused on the role of DEK in HPV positive cervical cancer cells, based on the observation that DEK was up-regulated by the high risk HPV E7 oncogene. We and others subsequently demonstrated that DEK is controlled by E2F/Rb pathways and thus also widely over-expressed in HPV negative cancers. DEK had been suspected to carry oncogenic activities since the early 1990s. In the past several years, we were able to prove such activities for the first time using organotypic epithelial raft cultures and classical keratinocyte transformation assays. Furthermore, we reported a new DEK knockout mouse model which was partially resistant to the development of chemically induced skin papillomas. Herein we propose to investigate the molecular role of DEK in head and neck squamous cell carcinoma (HNSCCs), which can be positive or negative for HPV in cancer patients.
In Aim 1, we will carry out DEK loss and gain of function studies in mice to determine the requirement and sufficiency for HNSCC development.
In Aim 2, we will investigate newly identified DEK activities in the regulation of b-catenin signaling, EMT, cellular invasion and self-renewal. These experiments will be performed in primary human HNSCC cells.
In Aim 3, we will carry out structure-function studies to map tumor-associated DEK domains and to identify nuclear DEK-interacting factors. The results will provide an important first step in advancing our understanding of molecular networks by which this versatile chromatin topology regulator activates oncogenic signaling and phenotypes in human cells (Aim 2) and HNSCC development in mice (Aim 1).
DEK upregulation has been clinically noted for many human tumor types, and DEK has thus been widely referred to as an oncogene. We have published that DEK supports the initial stages of cancer development, and generated the first preclinical model systems in which therapeutic DEK targeting approaches can now be tested. These models include organotypic epithelial rafts, human xenografts and DEK knockout mice. DEK inhibition selectively targeted epithelial tumor cells: acute DEK depletion caused the death and chemosensitization of cancer cells. However, DEK depletion did not affect normal cells to the same extent, and left differentiated cells which comprise the majority of human epithelium unaffected. HNC is a devastating disease with poor survival, and new approaches to diagnose and treat this disease are urgently needed. Preliminary data herein support critical roles for DEK in HNC growth, and also invasion and thus cancer cell dissemination. Thus DEK might be targeted in advanced cancers which are responsible for the great majority of HNC-related deaths. The application determines the role of DEK in the activation of b-catenin signaling pathways which we believe are a major contributor to HNC growth and spread in the human body. We anticipate that the results of the proposed studies in HNC will have broad implications for all cancers in which DEK is overexpressed. Based upon our preliminary and published findings, we postulate that DEK will be a useful diagnostic marker, and that its targeting - perhaps in conjunction with conventional chemotherapies - will improve therapeutic outcomes at both early and late cancer stages.
|Smith, Eric A; Krumpelbeck, Eric F; Jegga, Anil G et al. (2018) The nuclear DEK interactome supports multi-functionality. Proteins 86:88-97|
|Serrano-Lopez, Juana; Nattamai, Kalpana; Pease, Nicholas A et al. (2018) Loss of DEK induces radioresistance of murine restricted hematopoietic progenitors. Exp Hematol 59:40-50.e3|
|Smith, Eric A; Kumar, Bhavna; Komurov, Kakajan et al. (2017) DEK associates with tumor stage and outcome in HPV16 positive oropharyngeal squamous cell carcinoma. Oncotarget 8:23414-23426|
|Matrka, Marie C; Watanabe, Miki; Muraleedharan, Ranjithmenon et al. (2017) Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis. PLoS One 12:e0177952|
|Smith, Eric A; Gole, Boris; Willis, Nicholas A et al. (2017) DEK is required for homologous recombination repair of DNA breaks. Sci Rep 7:44662|
|Adams, Allie K; Bolanos, Lyndsey C; Dexheimer, Phillip J et al. (2015) IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival. Oncotarget 6:43395-407|
|Adams, A K; Hallenbeck, G E; Casper, K A et al. (2015) DEK promotes HPV-positive and -negative head and neck cancer cell proliferation. Oncogene 34:868-77|
|Privette Vinnedge, L M; Benight, N M; Wagh, P K et al. (2015) The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers. Oncogene 34:2325-36|
|Matrka, Marie C; Hennigan, Robert F; Kappes, Ferdinand et al. (2015) DEK over-expression promotes mitotic defects and micronucleus formation. Cell Cycle 14:3939-53|
|Adams, Allie K; Wise-Draper, Trisha M; Wells, Susanne I (2014) Human papillomavirus induced transformation in cervical and head and neck cancers. Cancers (Basel) 6:1793-820|
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