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

[en] 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.

Research Center/Unit :

Giga-Cancer - ULiège

Disciplines :

Biochemistry, biophysics & molecular biology
Oncology

Author, co-author :

Mottet, Denis ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases

Pirotte, Sophie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases

Lamour, Virginie ; Université de Liège - ULiège > Centre facultaire de rech. en cancérologie expérimentale

Hagedorn, M.

Javerzat, S.

Bikfalvi, A.

Bellahcene, Akeila ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases

Castronovo, Vincenzo ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire - GIGA-R : Labo de recherche sur les métastases

Verdin, Eric

Language :

English

Title :

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

Publication date :

2009

Journal title :

Oncogene

ISSN :

0950-9232

eISSN :

1476-5594

Publisher :

Nature Publishing Group, Basingstoke, United Kingdom

Volume :

Issue :

Pages :

243-56

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

European FP6 STROMA
European FP6 METABRE
F.R.S.-FNRS - Fonds de la Recherche Scientifique
CAC - Centre anticancéreux près l'Université de Liège asbl
Fonds Léon Fredericq
Interuniveristy Attraction Pole Program - Belgian Science Policy (IAP 5/31)
Télévie

Available on ORBi :

since 11 August 2009

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138

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