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HDAC4 represses p21(WAF1/Cip1) expression in human cancer cells through a Sp1-dependent, p53-independent mechanism.
- Source :
-
Oncogene [Oncogene] 2009 Jan 15; Vol. 28 (2), pp. 243-56. Date of Electronic Publication: 2008 Oct 13. - Publication Year :
- 2009
-
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.
- Subjects :
- Acetylation
Animals
Binding Sites
Bone Neoplasms pathology
Brain Neoplasms drug therapy
Brain Neoplasms pathology
Cell Line, Tumor metabolism
Chick Embryo
Cyclin-Dependent Kinase Inhibitor p21 genetics
Epigenesis, Genetic
Gene Knockdown Techniques
Glioblastoma drug therapy
Glioblastoma pathology
HeLa Cells drug effects
HeLa Cells metabolism
Histone Deacetylase Inhibitors
Histones metabolism
Humans
Neoplasm Proteins antagonists & inhibitors
Osteosarcoma pathology
Protein Processing, Post-Translational
RNA, Messenger biosynthesis
RNA, Neoplasm biosynthesis
Repressor Proteins antagonists & inhibitors
Tumor Suppressor Protein p53 antagonists & inhibitors
Tumor Suppressor Protein p53 physiology
Cyclin-Dependent Kinase Inhibitor p21 biosynthesis
Gene Expression Regulation, Neoplastic
Histone Deacetylases physiology
Neoplasm Proteins physiology
Repressor Proteins physiology
Sp1 Transcription Factor physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 28
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 18850004
- Full Text :
- https://doi.org/10.1038/onc.2008.371