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• W2045594104 abstract "Background: Sp1 protein is a sequence-specific, DNA-binding protein that is a part of the Specificity protein/Kruppel-like factor family of transcription factors which is critical in the regulation of cell growth, differentiation and apoptosis. In pancreatic adenocarcinoma, Sp1 overexpression has been correlated with tumor differentiation, clinical tumor staging, tumor metastasis, and patient survival. Combination treatments with Sp1 inhibitor and antiangiogenic compounds have also shown promising results in pancreatic tumors. However, the underlying mechanism by which Sp1 regulates cell survival in pancreatic cancer cells has not been addressed. Sp1 activity is tightly regulated by several posttranslational modifications, one of which is glycosylation. The enzyme responsible for glycosylation of Sp1 is O-GlcNAc transferase (OGT) which adds a single GlcNAc. In the current study we have evaluated the regulation of Sp1 activity by glycosylation, which also affects downstream pathways controlling survival in pancreatic cancer cells. Methods: Expression of Sp1 was studied in the different pancreatic cancer cell lines and mouse models at the RNA level by qRT-PCR and in the protein level by Western blot. Sp1 expression and activity was inhibited using the specific inhibitor mithramycin or by using siRNA against Sp1. Effect of Sp1 inhibition on viability was studied using an MTT based assay. Apoptosis was evaluated by caspase activity assay. Glycosylation of Sp1 was inhibited either by decreasing expression of O-GlcNAC transferase (OGT) by siRNA or by alloxan, a specific inhibitor. The effect of Sp1 activity, NFkB activity and HSP activity following inhibition of glycosylation was measured by dual luciferase reporter assay. Effect of inhibition of OGT and Sp1 on pancreatic cancer cell proliferation and migration was studied using ECIS (electric cell-substrate impedance sensing).Inhibition of Sp1 translocation to nucleus in response to inhibitor treatment was studied by confocal microscopy. Results: Sp1 was found to be 5-15 fold overexpressed in pancreatic cancer cell lines over non-tumorigenic ductal cells and between 5-10 fold over normal pancreas in xenotransplanted patient tumors in mice. Inhibition of Sp1 by mithramycin, or by siRNA, resulted in a loss in viability (30% of control). Similar loss is viability was also seen following inhibition of the glycosyltransferase (OGT) by siRNA (32% of control).Inhibition of glycosylation of Sp1 resulted in its accumulation in the cytosol of the pancreatic cancer cells. Survival of pancreatic cancer cells is attributed to high expression of heat shock proteins and a constitutively active NF-kB pathway. In order to see if altering glycosylation of Sp1 had an effect on expression of these proteins, reporter activity assay was performed following inhibition of Sp1 activity (by mithramycin), or expression (siRNA) or by inhibiting glycosylating enzyme. Both altering glycosylation as well as inhibition of Sp1 resulted in lowered activity of several survival pathways like NF-kB (30% of control) and Heat shock proteins (40% of control) and resulted in downregulation of apoptosis evading genes like survivin and Bcl2. Inhibition of glycosylation of Sp1 also resulted in decreased proliferation and migration of pancreatic cancer cells. Conclusion: This study showed down-regulation of either Sp1 expression or activity leads to pancreatic cancer cell death. Furthermore, glycosylation of Sp1 by OGT plays a vital role in regulating proliferation, migration, and survival of pancreatic cancer cells. Citation Format: Sulagna Banerjee, Veena Sangwan, Olivia McGinn, Tara Kendall Krosch, Nameeta Mujumder, Vikas Dudeja, Mackenzie Tiffany, Vickers M. Selwyn, Ashok K. Saluja. Cell survival in pancreatic cancer is regulated by glycosylation of the transcription factor Sp1. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B57." @default.
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• W2045594104 date "2012-07-15" @default.
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• W2045594104 title "Abstract B57: Cell survival in pancreatic cancer is regulated by glycosylation of the transcription factor Sp1." @default.
• W2045594104 doi "https://doi.org/10.1158/1538-7445.panca2012-b57" @default.
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