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HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism

Oncogene volume 28, pages 243–256 (2009)Cite this article

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 p21WAF1/Cip1gene. The HDACs that regulate p21WAF1/Cip1 are not fully identified. Using small interfering RNAs, we found that HDAC4 participates in the repression of p21WAF1/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 p21WAF1/Cip1 proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21WAF1/Cip1. Induction of p21WAF1/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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Acknowledgements

This work was supported by grants from European FP6 (STROMA and METABRE), the National Fund for Scientific Research (Belgium), the Centre Anti-Cancéreux près de l’Université de Liège, the Fonds Léon Frédéricq, TELEVIE and Interuniversity Attraction Pole Program–Belgian Science Policy (IAP 5/31). DM and AB are Research Associates at the National Fund for Scientific Research (Belgium). VL and SP are NFSR National Fund for Scientific Research fellows.

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  1. Metastasis Research Laboratory, GIGA-Cancer (Center for Experimental Cancer Research), University of Liège, Liège, Belgium

    D Mottet, S Pirotte, V Lamour, A Bellahcène & V Castronovo

  2. Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA, USA

    D Mottet & E Verdin

  3. ELAT (European Laboratory for Angiogenesis and Translational Research), Institut National de la Santé et de la Recherche Médical INSERM U920 (ex E0113), University of Bordeaux I, Talence, France

    M Hagedorn, S Javerzat & A Bikfalvi

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Mottet, D., Pirotte, S., Lamour, V. et al. HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism. Oncogene 28, 243–256 (2009). https://doi.org/10.1038/onc.2008.371

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