title: HDAC1 inactivation induces mitotic defect and caspase-independent autophagic cell death in liver cancer.
abstract: Histone deacetylases (HDACs) are known to play a central role in the regulation of several cellular properties interlinked with the development and progression of cancer. Recently, HDAC1 has been reported to be overexpressed in hepatocellular carcinoma (HCC), but its biological roles in hepatocarcinogenesis remain to be elucidated. In this study, we demonstrated overexpression of HDAC1 in a subset of human HCCs and liver cancer cell lines. HDAC1 inactivation resulted in regression of tumor cell growth and activation of caspase-independent autophagic cell death, via LC3B-II activation pathway in Hep3B cells. In cell cycle regulation, HDAC1 inactivation selectively induced both p21(WAF1/Cip1) and p27(Kip1) expressions, and simultaneously suppressed the expression of cyclin D1 and CDK2. Consequently, HDAC1 inactivation led to the hypophosphorylation of pRb in G1/S transition, and thereby inactivated E2F/DP1 transcription activity. In addition, we demonstrated that HDAC1 suppresses p21(WAF1/Cip1) transcriptional activity through Sp1-binding sites in the p21(WAF1/Cip1) promoter. Furthermore, sustained suppression of HDAC1 attenuated in vitro colony formation and in vivo tumor growth in a mouse xenograft model. Taken together, we suggest the aberrant regulation of HDAC1 in HCC and its epigenetic regulation of gene transcription of autophagy and cell cycle components. Overexpression of HDAC1 may play a pivotal role through the systemic regulation of mitotic effectors in the development of HCC, providing a particularly relevant potential target in cancer therapy.
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hong Jian
authors.initials: HJ
authors.lastname: Xie
authors.forename: Ji Heon
authors.initials: JH
authors.lastname: Noh
authors.forename: Jeong Kyu
authors.initials: JK
authors.lastname: Kim
authors.forename: Kwang Hwa
authors.initials: KH
authors.lastname: Jung
authors.forename: Jung Woo
authors.initials: JW
authors.lastname: Eun
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Bae
authors.forename: Min Gyu
authors.initials: MG
authors.lastname: Kim
authors.forename: Young Gyoon
authors.initials: YG
authors.lastname: Chang
authors.forename: Jung Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Hanna
authors.initials: H
authors.lastname: Park
authors.forename: Suk Woo
authors.initials: SW
authors.lastname: Nam
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003114:Colony-Forming Units Assay; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008156:Luciferases / Q000378:metabolism; D008938:Mitosis / Q000502:physiology*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016160:Retinoblastoma Protein; D016329:Sp1 Transcription Factor; D015533:Transcriptional Activation
chemical_list: C436291:CDKN1B protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D016329:Sp1 Transcription Factor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008156:Luciferases; D020169:Caspases; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1