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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1886-1893. Prepublished online as a Blood First Edition Paper on June 30, 2008; DOI 10.1182/blood-2008-03-143644. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-03-143644v1 112/5/1886    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rao, R. Articles by Bhalla, K. Search for Related Content PubMed PubMed Citation Articles by Rao, R. Articles by Bhalla, K. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA HDAC6 inhibition enhances 17-AAG–mediated abrogation of hsp90 chaperone function in human leukemia cells Rekha Rao1, Warren Fiskus1, Yonghua Yang1, Pearl Lee1, Rajeshree Joshi1, Pravina Fernandez1, Aditya Mandawat1, Peter Atadja2, James E. Bradner3, and Kapil Bhalla1 1 Medical College of Georgia (MCG) Cancer Center, Augusta; 2 Novartis Institute for Biomedical Research, Cambridge, MA; and 3 Dana-Farber Cancer Institute, Boston, MA Histone deacetylase 6 (HDAC6) is a heat shock protein 90 (hsp90) deacetylase. Treatment with pan-HDAC inhibitors or depletion of HDAC6 by siRNA induces hyperacetylation and inhibits ATP binding and chaperone function of hsp90. Treatment with 17-allylamino-demothoxy geldanamycin (17-AAG) also inhibits ATP binding and chaperone function of hsp90, resulting in polyubiquitylation and proteasomal degradation of hsp90 client proteins. In this study, we determined the effect of hsp90 hyperacetylation on the anti-hsp90 and antileukemia activity of 17-AAG. Hyperacetylation of hsp90 increased its binding to 17-AAG, as well as enhanced 17-AAG–mediated attenuation of ATP and the cochaperone p23 binding to hsp90. Notably, treatment with 17-AAG alone also reduced HDAC6 binding to hsp90 and induced hyperacetylation of hsp90. This promoted the proteasomal degradation of HDAC6. Cotreatment with 17-AAG and siRNA to HDAC6 induced more inhibition of hsp90 chaperone function and depletion of BCR-ABL and c-Raf than treatment with either agent alone. In addition, cotreatment with 17-AAG and tubacin augmented the loss of survival of K562 cells and viability of primary acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) samples. These findings demonstrate that HDAC6 is an hsp90 client protein and hyperacetylation of hsp90 augments the anti-hsp90 and antileukemia effects of 17-AAG. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Bots and R. W. Johnstone Rational Combinations Using HDAC Inhibitors Clin. Cancer Res., June 15, 2009; 15(12): 3970 - 3977. [Abstract] [Full Text] [PDF] K. N. Bhalla Combined Therapy with Agents Targeted against Deregulated Epigenetic Mechanisms in Cancer Am. Assoc. Cancer Res. Educ. Book, April 18, 2009; 2009(1): 233 - 236. [Full Text] [PDF]

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