DDB2 Regulates EMT in Oral SCC's and Transcriptionally Regulates HIF1A

An underlying hallmark of cancers is their ability to survive in hostile microenvironment marked by unrestrained proliferation acquired through genomic instability, which is often associated with a heightened propensity to accumulate DNA damage. Lack of understanding of molecular mechanisms that are compromised in cancers adds to further treatment complications of using traditional radiotherapy and classical chemotherapy. The role of damaged DNA binding proteins in launching a damaged DNA response (DDR) has been reported over the past several decades. But the role of these proteins in underlying tumor progression or outgrowth as tumor suppressors has just started to uncover. Here, I have investigated the role of Damaged DNA binding protein 2 (DDB2) as a candidate tumor suppressor gene in oral squamous cell carcinoma of the Head and Neck (HNSCC). DDB2, and its heterodimer DDB1, are involved in repair of UV induced damage lesions. The deficiency of these DNA repair proteins is associated with a condition known as Xeroderma pigmentosum (XP). XP is characterized by increased sun sensitivity and incidence of cancer. My work here revealed a novel tumor suppressor function of DDB2; suppressing hypoxia response by direct inhibition of hypoxia inducible factor, HIF1. HIF1 protein plays a major role in survival of aggressive tumor cells in hostile conditions by activating adaptive responses. My studies also corroborate a previous reported function of DDB2 in inhibiting epithelial to mesenchymal transition (EMT) in Oral SCC’s. Expression of DDB2 was significantly downregulated in various SCC cell lines. Interestingly, I found the levels of DDB1 were also downregulated, albeit only at protein level. It is increasingly evident from my studies that overexpression of DDB2 restored DDB1 protein levels in Oral SCC cell line, SCC-09, that expressed very low levels of DDB2. The EMT inducers such as VEGF, SNAIL, and ZEB1 that regulate epithelial (E-cadherin) and mesenchymal markers (N-Cadherin, Vimentin, and Fibronectin) are positively transcribed by HIF1A. My studies have convincingly revealed that overexpression of DDB2 reversed EMT in oral SCC cells, SCC-09, which expresses low DDB2 and originated from a metastatic oral cancer tissue. Most importantly, my studies unravel another transcriptional target of DDB2, that is HIF1A. I also found that levels of p300, a histone acetyltransferase and co-factor for HIF1A, were downregulated upon overexpression of DDB2. Hence, I describe another important role of DDB2 whereby (re) expression of DDB2, which acts as EMT regulator, can efficiently serve as repressor of HIF1 and further nip the expression of hypoxia inducible genes. This function of DDB2 is recognized as a double whammy for pre-malignant cells that look to acquire motility, via EMT, and develop into aggressive tumor cells with metastatic potential. DDB2 stands in the spotlight as a tumor suppressor gene that qualifies itself as a worthy contender to be considered during designing novel therapeutics in treatment of oral cancer.