Antitumor Effects in Hepatocarcinoma of lsoform-Selective Inhibition of HDAC2

Ilistone deacetylase 2 (IIDAC2) is a chromatin modifier involved in epigenetic regulation of cell cycle, apoptosis, and differentiation that is upregulated commonly in human hepatocellular carcinoma (HCC). In this study, we show that specific targeting of this HDAC isoforrn is sufficient to inhibit HCC progression. siRNA-mediated silencing of HDAC inhibited HCC cell growth by blocking cell-cycle progression and inducing apoptosis. These effects were associated with deregulation of HDAC-regulated genes that control cell cycle, apoptosis, and lipid metabolism, specifically, by upregulation of p27 and acetylated p53 and by downregulation of CDK6 and BCL2. We found that HDAC2 silencing in HCC cells also strongly inhibited PPARy signaling and other regulators of glycolysis (ChREBRY and GLUT4) and lipogenesis (SREBP1C and FAS), eliciting a marked decrease in fat: accumulation. Notably, systemic delivery of LIDAC2 siRNA encapsulated in lipid nanoparticles was sufficient to blunt the growth of human LICC in a murine xenograft model. Our findings offer preclinical proof-of-concept for LIDAC2 blockade as a systemic therapy for liver cancer. (C) 2014 AACR.