RRC ID 45136
Author Lee YH, Seo D, Choi KJ, Andersen JB, Won MA, Kitade M, Gómez-Quiroz LE, Judge AD, Marquardt JU, Raggi C, Conner EA, MacLachlan I, Factor VM, Thorgeirsson SS.
Title Antitumor effects in hepatocarcinoma of isoform-selective inhibition of HDAC2.
Journal Cancer Res.
Abstract Histone deacetylase 2 (HDAC2) 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 isoform 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 PPARγ signaling and other regulators of glycolysis (ChREBPα and GLUT4) and lipogenesis (SREBP1C and FAS), eliciting a marked decrease in fat accumulation. Notably, systemic delivery of HDAC2 siRNA encapsulated in lipid nanoparticles was sufficient to blunt the growth of human HCC in a murine xenograft model. Our findings offer preclinical proof-of-concept for HDAC2 blockade as a systemic therapy for liver cancer.
Volume 74(17)
Pages 4752-61
Published 2014-9-1
DOI 10.1158/0008-5472.CAN-13-3531
PII 0008-5472.CAN-13-3531
PMID 24958469
PMC PMC4155016
MeSH Animals Apoptosis / genetics Carcinoma, Hepatocellular / genetics* Carcinoma, Hepatocellular / pathology Cell Cycle / genetics Cell Line, Tumor Cyclin-Dependent Kinase 6 / genetics Disease Progression Down-Regulation / genetics Gene Expression Regulation, Neoplastic / genetics Glycolysis / genetics Hep G2 Cells Histone Deacetylase 2 / genetics* Humans Lipid Metabolism / genetics Lipogenesis / genetics Liver Neoplasms / genetics* Liver Neoplasms / pathology Male Mice Mice, SCID PPAR gamma / genetics Proliferating Cell Nuclear Antigen / genetics Protein Isoforms / genetics* Signal Transduction / genetics Tumor Suppressor Protein p53 / genetics Up-Regulation / genetics bcl-2-Associated X Protein / genetics
IF 8.378
Times Cited 24
Human and Animal Cells