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Antitumor Effects in Hepatocarcinoma of Isoform-Selective Inhibition of HDAC2.

 Yun-Han Lee  ;  Daekwan Seo  ;  Kyung-Ju Choi  ;  Jesper B. Andersen  ;  Min-Ah Won  ;  Mitsuteru Kitade  ;  Luis E. Gómez-Quiroz  ;  Adam D. Judge  ;  Jens U. Marquardt  ;  Chiara Raggi  ;  Elizabeth A. Conner  ;  Ian MacLachlan  ;  Valentina M. Factor  ;  Snorri S. Thorgeirsson 
 CANCER RESEARCH, Vol.74(17) : 4752-4761, 2014 
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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
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.
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1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Won, Min Ah(원민아)
Lee, Yun Han(이윤한)
Choi, Kyung Ju(최경주)
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