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J. Biol. Chem., Vol. 281, Issue 19, 13612-13619, May 12, 2006

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Histone Deacetylase Inhibitors Repress the Transactivation Potential of Hypoxia-inducible Factors Independently of Direct Acetylation of HIF-^*

From the Cardeza Foundation for Hematologic Research and Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors regulating the oxygen supply, glucose metabolism, and angiogenesis. HIF function requires the recruitment of p300/CREB-binding protein, two coactivators with histone acetyltransferase activity, by the C-terminal transactivation domain of HIF- (HIF-CAD). Histone deacetylase inhibitors (HDAIs) induce differentiation or apoptosis and repress tumor growth and angiogenesis, hence being explored intensively as anti-cancer agents. Using combined pharmacological, biochemical, and genetic approaches, here we show that HDAIs repress the transactivation potential of HIF-CAD. This repression is independent of the function of tumor suppressors von Hippel-Lindau or p53 or the degradation of HIF-. We also demonstrate the sufficiency of low concentrations of HDAIs in repression of HIF target genes in tumor cells. We further show that HDAIs induce hyperacetylation of p300 and repress the HIF-1·p300 complex in vivo. In vitro acetylation analysis reveals that the p300CH1 region, but not HIF-CAD, is susceptible to acetylation. Taken together, our data demonstrate that a deacetylase activity is indispensable for the transactivation potential of HIF-CAD and support a model that acetylation regulates HIF function by targeting HIF-·p300 complex, not by direct acetylating HIF-. The demonstration that HDAIs repress both HIF-1 and HIF-2 transactivation potential independently of von Hippel-Lindau tumor suppressor and p53 function indicates that HDAIs may have biological effects in a broad range of tissues in addition to tumors.

Received for publication, January 17, 2006 , and in revised form, March 15, 2006.

^* This work is supported in part by NCI, National Institutes of Health (NIH), Grants K01-CA098809 (to N. S.) and RO1-CA89212 (to J. C.) and W. W. Smith Trust Cancer Research Award C#0505 (to N. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains primer sequences.

¹ Present address: GlaxoSmithKline, Oncology, MMPD CEDD, UP1450, 1250 S. Collegeville Rd., Collegeville, PA 19426.

² Supported in part by NCI, NIH, Grant R25CA048010.

³ Present address: Dept. of Urology, Huashan Hospital of Shanghai Medical College, Fudan University, Shanghai, China, 200032.

⁴ To whom correspondence should be addressed: Cardeza Foundation and Dept. of Medicine, 1015 Walnut St., Curtis Bldg., Rm. 711, Philadelphia, PA 19107. Tel.: 215-955-5118; Fax: 215-955-2366; E-mail: nianli.sang{at}jefferson.edu.

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