title: Antitumor effects in hepatocarcinoma of isoform-selective inhibition of HDAC2.
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.
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea. snorri_thorgeirsson@nih.gov yhlee87@yuhs.ac.
authors: Yun-Han
authors: YH
authors: Lee
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors: Daekwan
authors: D
authors: Seo
authors: Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea.
authors: Kyung-Ju
authors: KJ
authors: Choi
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors: Jesper B
authors: JB
authors: Andersen
authors: Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea.
authors: Min-Ah
authors: MA
authors: Won
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors: Mitsuteru
authors: M
authors: Kitade
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors: Luis E
authors: LE
authors: Gómez-Quiroz
authors: Tekmira Pharmaceuticals, Corp., Burnaby, British Columbia, Canada.
authors: Adam D
authors: AD
authors: Judge
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors: Jens U
authors: JU
authors: Marquardt
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors: Chiara
authors: C
authors: Raggi
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors: Elizabeth A
authors: EA
authors: Conner
authors: Tekmira Pharmaceuticals, Corp., Burnaby, British Columbia, Canada.
authors: Ian
authors: I
authors: MacLachlan
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors: Valentina M
authors: VM
authors: Factor
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. snorri_thorgeirsson@nih.gov yhlee87@yuhs.ac.
authors: Snorri S
authors: SS
authors: Thorgeirsson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006019:Glycolysis / Q000235:genetics; D056945:Hep G2 Cells; D056464:Histone Deacetylase 2 / Q000235:genetics*; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D050155:Lipogenesis / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D047495:PPAR gamma / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D047495:PPAR gamma; D018809:Proliferating Cell Nuclear Antigen; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C413374:p27 antigen; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2