Evaluation of epigenetic modulation of cyclooxygenase-2 as a prognostic marker for hepatocellular carcinoma

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivative Works 3.0 Unported License.Cyclooxygenases (COX-1 and 2) catalyze the first step in prostanoid biosynthesis. They are implicated in homeostatic processes with an important role in inflammation and carcinogenesis. In the liver, COX-2 expression is restricted to proliferation or dedifferentiation situations. The COX-2 promoter contains numerous CpG islands that, when hypermethylated, result in transcriptionally silencing thus regulating the growth of carcinoma cells. In this work, we investigated whether a correlation exists between COX-2 expression and methylation signatures at the 5′region of the gene in hepatoma cell lines and human hepatocellular carcinoma (HCC). We also examined the acetylation status of the COX-2 promoter and the effects of histone deacetylase (HDAC) inhibitors on COX-2 expression. Our results suggest a significant association between reduced COX-2 expression and promoter hypermethylation of COX-2 and histone deacetylation in some hepatoma cell lines and in HCC. Treatment with demethylating agents or HDAC inhibitors restored the expression of COX-2. Moreover, in an HCC cohort, a statistically significant inverse association was observed between COX-2 mRNA levels and promoter methylation. In agreement with these data, a reduction of overall survival of the patients was observed after decreased COX-2 expression by promoter hypermethylation and histone H3 hypoacetylation.This work was supported by the Ministry of Science and Innovation (SAF2010-16037, SAF2009-12602 and BFU2011-24760) and by Comunidad de Madrid (P2010/BMD-2378). CIBERehd is funded by the Instituto de Salud Carlos III. AF-A and NA were supported by the Carlos III Health Institute (Red de Centros FIS-RECAVA RD06/0014/0025).Peer Reviewe