Histone Deacetylase 3 Inhibitor Suppresses Hepatitis C Virus Replication by Regulating Apo-A1 and LEAP-1 Expression

Abstract

Histone deacetylase (HDAC) inhibitors show clinical promise for the treatment of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the effect of HDAC inhibitor treatment on hepatitis C virus (HCV) replication in Huh7 human liver cells and in a mouse model of HCV infection. Viral replication was markedly suppressed by the HDAC3 inhibitor at concentrations below 1 mmol/L, with no cellular toxicity. This was accompanied by upregulation of liver-expressed antimicrobial peptide 1(LEAP-1) and downregulation of apolipoprotein-A1 (Apo-A1), as determined by microarray and quantitative RT-PCR analyses. Moreover, HDAC3 was found to modulate the binding of CCAAT-enhancer-binding protein a (C/EBPa), hypoxia-inducible factor 1a (HIF1a), and signal transducer and activator of transcription 3 (STAT3) to the LEAP-1 promoter. HDAC3 inhibitor treatment also blocked HCV replication in a mouse model of HCV infection. These results indicate that epigenetic therapy with HDAC3 inhibitor may be a potential treatment for diseases associated with HCV infection such as HCC.

<p>RGFP966 Suppresses Tumor Growth and Migration Through Inhibition of EGFR Expression in Hepatocellular Carcinoma Cells in vitro</p>

“…7 A recent study reported that HDAC3 participates in hepatitis C virus (HCV) replication, and RGFP966 may be a potential treatment for diseases associated with HCV infection such as HCC, although no change in cell viability following treatment of 10μM RGFP966 in HCV-infected Huh7 cells. 20 In accordance with this report, we found that RGFP966 mildly inhibits cell proliferation of Huh7 and HepG2 cells at a higher concentration, whereas remarkable inhibitory effect was shown in PLC/PRF/ 5 cells following treatment of 10μM RGFP966 (Figure 1). EGFR, a receptor tyrosine kinase, is overexpressed in a significant proportion of hepatocellular carcinomas and can be phosphorylated at different tyrosine sites, leading to subsequent activation of different pathways.…”

Gene Expression Profiling of Different Huh7 Variants Reveals Novel Hepatitis C Virus Host Factors

“…THAP7 is a chromatin-associated transcriptional repressor that binds to H3 and H4 histone tails, recruits chromatin modifiers, like histone deacetylase 3 (HDAC3) or nuclear receptor co-repressor 1 (NCOR1), and leads to repression of gene expression via deacetylation of target loci [95,96]. It is conceivable that THAP7 recruits HDAC3 to genes restricting HCV replication, as it has been shown that HDAC3 inhibitors suppress HCV replication in Huh7 cells and in a mouse model [97,98]. This in line with our finding in that THAP7 silencing suppresses HCV replication in Huh7-Lunet cells.…”

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1

“…Given the large variation of their substrates, HDACs regulate diverse physiological processes, in addition to their epigenetic role. Their aberrant activity is linked to different pathologies such as cardiac hypertrophy [30,31], neurodegenerative diseases [32,33], viral infections [34,35], and cancer [36,37]. As a result, a lot of effort has been devoted to the development of HDAC inhibitors (HDACi) to fully reveal their physiological role.…”