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

FERNÁNDEZ ALVAREZ, ANA JULIA; LLORENTE-IZQUIERDO, ANA C.; MAYORAL MONIBAS, RAFAEL; AGRA ANDRIEU, NOELIA; BOSCÁ, LISARDO; CASADO PINNA, MARTA; MARTÍN-SANZ, PALOMA

Oncogenesis

Nature Publishing Group

Año: 2012 vol. 1 p. 1 - 11

2157-9024

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.