Journal
ONCOGENE
Volume 28, Issue 2, Pages 243-256Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2008.371
Keywords
histone deacetylase; p21(WAF1/Cip1); Sp1; siRNA; cancer
Funding
- European FP6 (STROMA and METABRE)
- National Fund for Scientific Research (Belgium)
- Centre Anti-Cancereux pres de l'Universite de Liege
- Fonds Leon Fredericq
- TELEVIE and Interuniversity Attraction Pole Program-Belgian Science Policy [IAP 5/31]
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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 transcriptionalreac tivation 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.
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