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J. Biol. Chem., Vol. 280, Issue 51, 42433-42441, December 23, 2005

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Regulation of the INK4a/ARF Locus by Histone Deacetylase Inhibitors^*

From the Molecular Oncology Program, Spanish National Cancer Center (CNIO), 28029 Madrid, Spain

Despite the importance of the INK4a/ARF locus in tumor suppression, its modulation by histone deacetylase inhibitors (HDACis) remains to be characterized. Here, we have shown that the levels of p16^INK4a are decreased in human and murine fibroblasts upon exposure to relatively high concentrations of trichostatin A and sodium butyrate. Interestingly, the levels of p19^ARF are strongly upregulated in murine cells even at low concentrations of HDACis. Using ARF-deficient cells, we have demonstrated that p19^ARF plays an active role in HDACi-triggered cytostasis and the contribution of p19^ARF to this arrest is of higher magnitude than that of the well established HDACi target p21^Waf1/Cip. Moreover, chemically induced fibrosarcomas in ARF-null mice are more resistant to the therapeutic effect of HDACis than similar tumors in wild type or p21^Waf1/Cip-null mice. Together, our results have established the tumor suppressor ARF as a relevant target for HDACi chemotherapy.

Received for publication, July 28, 2005 , and in revised form, September 20, 2005.

^* This work was supported in part by European Union Grants QLRT-2000-00616, QLRT-2000-02084, and LSHC-CT-2003-506803 and the Spanish Ministry of Science and Technology (SAF2002-03402). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a fellowship from the Spanish Ministry of Education.

² To whom correspondence should be addressed: Molecular Oncology Program, Spanish National Cancer Center (CNIO), Melchor Fernández Almagro St. 3, 28029 Madrid, Spain. Tel.: 34-917328032; Fax: 34-917328028; E-mail: mserrano{at}cnio.es.

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