Abstract
Cancer cells have complex, unique characteristics that distinguish them from normal cells, such as increased growth rates and evasion of anti-proliferative signals. Global inhibition of class I and II histone deacetylases (HDACs) stops cancer cell proliferation in vitro and has proven effective against cancer in clinical trials, at least in part, through transcriptional reactivation of the p21(WAF1/Cip1)gene. The HDACs that regulate p21(WAF1/Cip1) are not fully identified. Using small interfering RNAs, we found that HDAC4 participates in the repression of p21(WAF1/Cip1) through Sp1/Sp3-, but not p53-binding sites. HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21(WAF1/Cip1) proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21(WAF1/Cip1). Induction of p21(WAF1/Cip1) mediated by silencing of HDAC4 arrested cancer cell growth in vitro and inhibited tumor growth in an in vivo human glioblastoma model. Thus, HDAC4 could be a useful target for new anti-cancer therapies based on selective inhibition of specific HDACs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Animals
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Binding Sites
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Bone Neoplasms / pathology
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Brain Neoplasms / drug therapy
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Brain Neoplasms / pathology
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Cell Line, Tumor / metabolism
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Chick Embryo
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Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis*
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Epigenesis, Genetic
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Gene Expression Regulation, Neoplastic*
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Gene Knockdown Techniques
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Glioblastoma / drug therapy
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Glioblastoma / pathology
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HeLa Cells / drug effects
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HeLa Cells / metabolism
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Histone Deacetylase Inhibitors
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Histone Deacetylases / physiology*
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Histones / metabolism
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Humans
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / physiology*
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Osteosarcoma / pathology
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Protein Processing, Post-Translational
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RNA, Messenger / biosynthesis
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RNA, Neoplasm / biosynthesis
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / physiology*
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Sp1 Transcription Factor / physiology*
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Tumor Suppressor Protein p53 / antagonists & inhibitors
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Tumor Suppressor Protein p53 / physiology
Substances
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Histone Deacetylase Inhibitors
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Histones
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Neoplasm Proteins
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RNA, Messenger
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RNA, Neoplasm
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Repressor Proteins
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Sp1 Transcription Factor
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Tumor Suppressor Protein p53
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HDAC4 protein, human
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Histone Deacetylases