Abstract A58: Epigenetic regulation of CpG promoters by NF-kB pathway in invasive pancreatic cancer cells.

Abstract

Abstract Pancreatic cancer is one of the most common causes of cancer death internationally. The diagnosis of early-stage pancreatic cancer often has a poor prognosis and the survival rate is quite low once it becomes advanced or metastatic. Epigenetic modifications such as DNA methylation play a significant role during both normal human development and cancer progression. We sought to investigate which genes are epigenetically regulated in the invasive population of pancreatic cancer cells. We conducted epigenetic arrays in both PANC1 and HPAC pancreatic cancer cell lines and compared the global DNA methylation status of CpG promoters in invasive cells to their non-invasive counterparts. The differentially methylated genes were applied into Ingenuity pathway analysis and our results showed that the NF-kB pathway is one of the top activated pathways in invasive cells. In line with this, we determined that upon treatment with NF-kB pathway inhibitors, the invasive and migratory ability of total cells are significantly disrupted. Moreover, the SRY-box transcription factor SOX9, which is demethylated in invasive cells, is shown to play a crucial role in invasion of both cell lines. In addition, we found a potential NF-kB binding site located in the SOX9 promoter in Genomatix database. Interestingly, the NF-kB subunit p65 positively regulates SOX9 expression by binding to its promoter directly, which is enhanced by treatment of demethylation agents. Thus, our work establishes a link between the classical NF-kB signaling transduction pathway and pancreatic cancer cell invasion. We believe our data can result in the identification of novel signals and molecules at an epigenetic level that can potentially be targeted in pharmaceutical investigations and clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A58.