Abstract 2410: Reduced expression of DDB2 promotes epithelial to mesenchymal transition in colon cancer

Abstract

Abstract Invasion and metastasis are the hallmarks of malignant tumor progression and the principal cause of death related to solid tumors. Epithelial to mesenchymal transition (EMT) is intricately associated with cancer progression, as it confers cancer cells the ability to invade and metastasize to a distant organ. Here we identify a novel function of nucleotide excision repair protein DDB2 as an important antagonist of the EMT in colon carcinoma through its maintenance of epithelial phenotype. In human colon carcinoma samples, loss of DDB2 expression is highly correlated with the aggressiveness of the disease. Moreover, stimuli (TGF-beta and hypoxia) that induce EMT inhibit expression of DDB2; and loss of DDB2 is sufficient to promote EMT of colon cancer cells. The mechanism involves DDB2 mediated transcriptional repression of VEGF and MMP3. DDB2 represses these genes by histone deacetylation. We also observed that loss of DDB2 results in resistance to anoikis, an important barrier to metastasis. The lack of anoikis response is associated with increased Akt and ERK activity. Furthermore, treatment with Phenethyl Isothiocyanate (PEITC), a promising cancer chemopreventive component, augmented E-cadherin expression that is related to an increase in DDB2 expression. The present study suggests that anti-metastatic effect of PEITC involves important role of DDB2. Together, our results show that loss of DDB2 expression is both necessary and sufficient for EMT during colon carcinoma progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2410. doi:1538-7445.AM2012-2410