DDB2 regulates Epithelial-to-Mesenchymal Transition (EMT) in Oral/Head and Neck Squamous Cell Carcinoma
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Prashant V. Bommi1,3, Sriram Ravindran1, Pradip Raychaudhuri2 and Srilata Bagchi1
1Department of Oral Biology, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, USA
2Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
3Current Address: Department of Clinical Cancer Prevention, Biological Sciences Research Building (BSRB), University of Texas MD Anderson Cancer Center, Houston, Texas
Srilata Bagchi, email: firstname.lastname@example.org
Keywords: oral/head and neck squamous cell carcinoma (HNSCC); damaged DNA binding protein 2 (DDB2); epithelial-to-mesenchymal transition (EMT); transforming growth factor beta (TGFβ); tumor suppressor
Received: June 09, 2018 Accepted: September 08, 2018 Published: October 5, 2018
DDB2 is a sensor of DNA damage and it plays an important role in Global Genomic Repair (GG-NER). Our previous studies show that DDB2 is involved in the regulation of metastasis in colon adenocarcinoma. Squamous Cell Carcinomas in the Oral/Head & Neck region (HNSCC) are particularly aggressive due to high incidence of recurrence and distant metastasis. In this study, we show that DDB2 expression is downregulated in advanced HNSCCs and loss of DDB2 expression coincides with reduced survival. Recent meta-analysis of gene expression data characterized the mesenchymal-type (EMT-type) as one most aggressive cancer cluster in HNSCC. Here, we report that DDB2 constitutively represses mRNA expression of the EMT- regulatory transcription factors SNAIL, ZEB1, and angiogenic factor VEGF in HNSCC cells. As a result, re-expression of DDB2 in metastatic cells reversed EMT with transcriptional upregulation of epithelial marker E-cadherin, and downregulation of mesenchymal markers N-cadherin, Vimentin, and Fibronectin. Interestingly, in a reverse assay, depletion of DDB2 in non-metastatic cells induced expression of the same EMT-regulatory transcription factors. TGFβs are major regulators of Snail and Zeb1, and we observed that DDB2 transcriptionally regulates expression of TGFB2 in HNSCC cells. Re-expression of DDB2 in mouse embryonic fibroblasts (MEFs) isolated from Ddb2 (−/−) knockout-mice resulted in repression of EMT-regulatory factors Zeb1, Snail and Tgfb2. Taken together, these results support the active role of DDB2 as a candidate suppressor of the EMT-process in HNSCC. Early detection leads to significantly higher survival in HNSCC and DDB2 expression in tumors can be a predictor of EMT progression.
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