HDAC4 represses p21(WAF1/Cip1) expression in human cancer cells through a Sp1-dependent, p53-independent mechanism.

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.

• Authors: D Mottet, S Pirotte, V Lamour, M Hagedorn, S Javerzat, A Bikfalvi, A Bellahcène, E Verdin, V Castronovo
• Journal: Oncogene (Oncogene) Vol. 28 Issue 2 Pg. 243-56 (Jan 15 2009) ISSN: 1476-5594 [Electronic] England
• PMID: 18850004 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Histone Deacetylase Inhibitors
• Histones
• Neoplasm Proteins
• RNA, Messenger
• RNA, Neoplasm
• Repressor Proteins
• Sp1 Transcription Factor
• Tumor Suppressor Protein p53
• HDAC4 protein, human
• Histone Deacetylases

Topics

• Acetylation
• Animals
• Binding Sites
• Bone Neoplasms (pathology)
• Brain Neoplasms (drug therapy, pathology)
• Cell Line, Tumor (metabolism)
• Chick Embryo
• Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis, genetics)
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Glioblastoma (drug therapy, pathology)
• HeLa Cells (drug effects, metabolism)
• Histone Deacetylase Inhibitors
• Histone Deacetylases (physiology)
• Histones (metabolism)
• Humans
• Neoplasm Proteins (antagonists & inhibitors, physiology)
• Osteosarcoma (pathology)
• Protein Processing, Post-Translational
• RNA, Messenger (biosynthesis)
• RNA, Neoplasm (biosynthesis)
• Repressor Proteins (antagonists & inhibitors, physiology)
• Sp1 Transcription Factor (physiology)
• Tumor Suppressor Protein p53 (antagonists & inhibitors, physiology)