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J. Biol. Chem., Vol. 281, Issue 9, 5612-5622, March 3, 2006

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Suberoylanilide Hydroxamic Acid Potentiates Apoptosis, Inhibits Invasion, and Abolishes Osteoclastogenesis by Suppressing Nuclear Factor-B Activation^*

Yasunari Takada¹, Ann Gillenwater, Haruyo Ichikawa, and Bharat B. Aggarwal²

From the Cytokine Research Laboratory, Departments of Experimental Therapeutics and Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Because of its ability to suppress tumor cell proliferation, angiogenesis, and inflammation, the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) is currently in clinical trials. How SAHA mediates its effects is poorly understood. We found that in several human cancer cell lines, SAHA potentiated the apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents and inhibited TNF-induced invasion and receptor activator of NF-B ligand-induced osteoclastogenesis, all of which are known to require NF-B activation. These observations corresponded with the down-regulation of the expression of anti-apoptotic (IAP1, IAP2, X chromosome-linked IAP, Bcl-2, Bcl-x_L, TRAF1, FLIP, and survivin), proliferative (cyclin D1, cyclooxygenase 2, and c-Myc), and angiogenic (ICAM-1, matrix metalloproteinase-9, and vascular endothelial growth factor) gene products. Because several of these genes are regulated by NF-B, we postulated that SAHA mediates its effects by modulating NF-B and found that SAHA suppressed NF-B activation induced by TNF, IL-1, okadaic acid, doxorubicin, lipopolysaccharide, H₂O₂, phorbol myristate acetate, and cigarette smoke; the suppression was not cell type-specific because both inducible and constitutive NF-B activation was inhibited. We also found that SAHA had no effect on direct binding of NF-B to the DNA but inhibited sequentially the TNF-induced activation of IB kinase, IB phosphorylation, IB ubiquitination, IB degradation, p65 phosphorylation, and p65 nuclear translocation. Furthermore, SAHA inhibited the NF-B-dependent reporter gene expression activated by TNF, TNFR1, TRADD, TRAF2, NF-B-inducing kinase, IB kinase, and the p65 subunit of NF-B. Overall, our results indicated that NF-B and NF-B-regulated gene expression inhibited by SAHA can enhance apoptosis and inhibit invasion and osteoclastogenesis.

Received for publication, July 5, 2005 , and in revised form, November 18, 2005.

^* This work was supported in part by a grant from the Clayton Foundation for Research, Department of Defense U. S. Army Breast Cancer Research Program Grant BC010610, National Institutes of Health PO1 Grant CA91844 on lung chemoprevention, and National Institutes of Health P50 Head and Neck SPORE Grant P50CA97007 (all to B. B. A.) and grants from the Odyssey Program and the Theodore N. Law Award for Scientific Achievement Fund from The University of Texas M. D. Anderson Cancer Center (to Y. T.). 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 An Odyssey Program Special Fellow at The University of Texas M. D. Anderson Cancer Center.

² A Ransom Horne, Jr., Distinguished Professor of Cancer Research. To whom correspondence should be addressed: Cytokine Research Laboratory, Dept. of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-792-3503/6459; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org.

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