Histone Deacetylase Inhibition Restores Expression of Hypoxia-Inducible Protein NDRG1 in Pancreatic Cancer: An Advance Study

Objectives: The hypoxia-inducible and differentiation-related protein N-myc downstream-regulated gene-1 (NDRG1) is a potential biomarker in pancreatic cancer. The effects of the differentiating histone deacetylase inhibitor trichostatin A (TSA) in human pancreatic cancer cell lines representing different tumour stages were investigated because NDRG1 expression is diminished in high-grade tumours. Cancer is a genetic disease characterized by inherited or sporadic mutations in tissue homeostasis, cell cycle control, and apoptosis genes.

Methods: TSA was used to treat PANC-1 (poorly differentiated) and Capan-1 (moderately to well-differentiated) cells. Microscopic analyses, colorimetric assays, cell counts, real-time polymerase chain reaction, and Western blotting were used to evaluate the effects in vitro.

Results: PANC-1 cells were treated with 0.5 M TSA for four days. Cellular differentiation was restored, proliferation was suppressed, and p21Cip1 protein expression was increased. Trichostatin A upregulated NDRG1 mRNA and protein levels under normoxia from day 1 and by 6-fold by day 4 (P < 0.01 at all time points). After 24 hours under hypoxia, NDRG1 expression was further in-creased in differentiated cells (P < 0.01). Other hypoxia-regulated genes showed positive changes in their expression.

Conclusions: Histone deacetylase inhibitors have the potential to be a novel epidrug for pancreatic cancer, as they reverse the undifferentiated phenotype, helping patients to overcome resistance and respond better to traditional cytotoxic treatments.