Gene expression analysis of HDAC and KDMs indicates a prognostic role for HDAC11 in hepatocellular carcinoma

Abstract Histone deacetylases (HDACs) and lysine demethylases (KDMs) are key epigenetic enzymes regulating chromatin structure and gene transcription. Aberrant expression of those epigenetic modifiers has been extensively documented in cancer, but their role in hepatocellular carcinoma (HCC) is yet undefined. In this study, we aimed to analyze the expression of specific components of HDACs and KDMs in the liver tissue of HCC patients and evaluate the possible association with clinical outcome. Fifty-four patients with HCC of nonviral etiology were enrolled and followed-up for clinical and biochemical parameters after curative surgery. Gene expression of HDAC11 , KDM5D , KDM6B , and KDM8 was assessed in HCC tissues and homologous non-neoplastic liver tissues by RealTime q-PCR. For a subset of patients, total HDAC enzymatic activity in nuclear extracts from liver tissues was assessed. HDAC11 was upregulated in 32 and downregulated in 19 HCC samples. In contrast, KDMs genes resulted mostly downregulated in HCC. Kaplan-Meier survival analysis revealed that patients with HDAC11 upregulation had a significantly higher mortality rate than those with HDAC11 downregulation ( p = 0.041). Furthermore, Cox regression analysis showed that HDAC11 expression was a predictor of mortality with a hazard ratio (HR) of 2.29 (95% CI, 1.01–5.22; p = 0.04). This mortality risk even increased when adjusted for age, sex, C-reactive protein, creatinine, albumin, alpha fetoprotein, lipid parameters, microvascular invasion and tumor differentiation degree. These findings highlight a possible prognostic role for HDAC11 in HCC and suggest to consider the potential of targeting histone-modifying enzymes for future therapeutic strategy.