Aberrant regulation of HDAC2 mediates proliferation of hepatocellular carcinoma cells by deregulating expression of G1/S cell cycle proteins

• Published in: PloS one 2011-11, Vol.6 (11), p.e28103
• Main Authors: Noh, Ji Heon, Jung, Kwang Hwa, Kim, Jeong Kyu, Eun, Jung Woo, Bae, Hyun Jin, Xie, Hong Jian, Chang, Young Gyoon, Kim, Min Gyu, Park, Won Sang, Lee, Jung Young, Nam, Suk Woo
• Format: Article
• Language: English
• Subjects: Aberration; Animals; Apoptosis; Binding Sites; Biology; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - pathology; Chromatin; Cyclin D1; Cyclin-dependent kinase 2; Cyclin-dependent kinase 4; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Deoxyribonucleic acid; Deregulation; Disruption; DNA; DNA biosynthesis; DNA synthesis; E2F protein; Embryogenesis; Embryonic development; Embryonic growth stage; Enzyme Activation - drug effects; G1 Phase - drug effects; G1 Phase - genetics; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Targeting; Genes; HDAC2 protein; Hepatocellular carcinoma; Histone deacetylase; Histone Deacetylase 2 - metabolism; Histone Deacetylase Inhibitors - pharmacology; Humans; Immune response; INK4a protein; Liver; Liver cancer; Liver Neoplasms - enzymology; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Medicine; Mice; Mitogens - pharmacology; p16 Protein; Pathology; Phosphorylation; Promoter Regions, Genetic - genetics; Prostate cancer; Protein Binding - drug effects; Proteins; Proto-Oncogene Proteins c-myc - metabolism; Reduction; S Phase - drug effects; S Phase - genetics; Signaling; Solid tumors; Sp1 protein; Sp1 Transcription Factor - metabolism; Transcription; Transcription, Genetic - drug effects; Tumors; Wnt Signaling Pathway - drug effects; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0028103

Histone deacetylase 2 (HDAC2) is crucial for embryonic development, affects cytokine signaling relevant for immune responses and is often significantly overexpressed in solid tumors; but little is known about its role in human hepatocellular carcinoma (HCC). In this study, we showed that targeted-disruption of HDAC2 resulted in reduction of both tumor cell growth and de novo DNA synthesis in Hep3B cells. We then demonstrated that HDAC2 regulated cell cycle and that disruption of HDAC2 caused G1/S arrest in cell cycle. In G1/S transition, targeted-disruption of HDAC2 selectively induced the expression of p16(INK4A) and p21(WAF1/Cip1), and simultaneously suppressed the expression of cyclin D1, CDK4 and CDK2. Consequently, HDAC2 inhibition led to the down-regulation of E2F/DP1 target genes through a reduction in phosphorylation status of pRb protein. In addition, sustained suppression of HDAC2 attenuated in vitro colony formation and in vivo tumor growth in a mouse xenograft model. Further, we found that HDAC2 suppresses p21(WAF1/Cip1) transcriptional activity via Sp1-binding site enriched proximal region of p21(WAF1/Cip1) promoter. In conclusion, we suggest that the aberrant regulation of HDAC2 may play a pivotal role in the development of HCC through its regulation of cell cycle components at the transcription level providing HDAC2 as a relevant target in liver cancer therapy.