Céline Tiffon
University Hospital Bern, Switzerland
Title: Histone deacetylase inhibition restores expression of hypoxia-inducible protein NDRG1 in pancreatic cancer
Biography
Biography: Céline Tiffon
Abstract
Pancreatic ductal adenocarcinoma, the most common subtype of human pancreatic cancer, affects both men and women and is highly aggressive, with a five-year survival rate of only about 5%. N-myc Downstream-Regulated Gene-1 (NDRG1) is a hypoxia-inducible and differentiation-related protein and candidate biomarker in pancreatic cancer. As NDRG1 expression is lost in high-grade tumors, the effects of the differentiating histone deacetylase inhibitor trichostatin A (TSA) were examined in human pancreatic cancer cell lines representing different tumor grades. Panc-1 (poorly differentiated) and Capan-1 (moderately- to well-differentiated) cells were treated with TSA. Effects were assessed in vitro by microscopic analysis, colorimetric assays, cell counts, real-time polymerase chain reaction, and western blotting. Treatment of Panc-1 cells over four days with 0.5 µM TSA restored cellular differentiation, inhibited proliferation, and enhanced p21Cip1 protein expression. TSA upregulated NDRG1 mRNA and protein levels under normoxia from day one and by six-fold by day four (p<0.01 at all-time points). After 24 h under hypoxia, NDRG1 expression was further increased in differentiated cells (p<0.01). Favorable changes were identified in the expression of other hypoxia-regulated genes. HDAC inhibitors offer a potential novel epi-drug approach for pancreatic cancer by reversing the undifferentiated phenotype and allowing patients to overcome resistance and better respond to conventional cytotoxic treatments. Restoration of NDRG1 expression may represent a biomarker of malignant pancreatic tumors undergoing re-differentiation and redirecting toward a lower tumor grade. The use of the human ductal Panc-1 cell line treated with TSA represents a useful tool to study cellular differentiation through epigenetic mechanisms.