Role of DDB2 in Senescence and EMT
thesisposted on 2015-02-22, 00:00 authored by Nilotpal Roy
DDB2 (Damaged DNA Binding Protein 2) is a DNA repair protein initially identified as a key player in nucleotide excision repair. Several recent studies indicated potential tumor suppressor functions of DDB2. Towards that, I identified two new tumor suppressor functions of DDB2: inhibition of epithelial to mesenchymal transition (EMT) and induction of senescence. My studies revealed that DDB2 deficient cells do not undergo premature senescence after culture shock, exogenous oxidative stress, oncogenic stress or DNA damage. The deficiency in senescence was resulted from lack of ROS accumulation. Further investigation revealed that DDB2 causes ROS accumulation by epigenetically inhibiting expression of two important anti-oxidant genes, MnSOD and Catalase. These findings were further substantiated in mice by using chemical carcinogen induced liver fibrosis model and UV induced skin carcinogenesis model. As an extension of my work on delineating tumor suppressive role of DDB2, I investigated the role of DDB2 in colon cancer because reduced DDB2 expression is correlated with aggressive progression of colon cancer. Moreover, loss of DDB2 increases tumorigenecity of colon cancer cells in vitro and in vivo. A closer analyses attributed this increased tumorigenecity phenotype to a regulation of EMT and resistance to anoikis. Further findings indicated that the EMT regulation by DDB2 is related to transcriptional repression of VEGF, Snail1 and Zeb1. Concordantly, DDB2 deficient colon carcinoma cells are more metastatic in nature. Thus, loss of DDB2 expression results in a deficiency in senescence and increased EMT leading to an aggressive cancer progression. Hence, targeting DDB2 expression would be beneficial from therapeutic perspective. Towards that, I have used a naturally occurring compound Phenethyl Isothiocyanate (PEITC), currently in clinical trial, to elevate expression of DDB2 and inhibit tumorigenesis in mice. Together, my observation provides new insights on the role of DDB2 as a tumor suppressor through its regulation of senescence and metastasis related to EMT. These functions of DDB2 involve its role in transcription repression. Also, my work shows how DDB2 can be therapeutically targeted for the treatment of colon cancer.