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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.
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Submitted March 5, 2008
Accepted June 9, 2008
HDAC6 inhibition enhances 17-AAG-mediated abrogation of hsp90 chaperone function in human leukemia cells
Rekha Rao, Warren Fiskus, Yonghua Yang, Pearl Lee, Rajeshree Joshi, Pravina Fernandez, Aditya Mandawat, Peter Atadja, James E. Bradner, and Kapil Bhalla*
MCG Cancer Center, Medical College of Georgia, Augusta, GA, United States
Biomedical Research, Novartis Institute for Biomedical Research Inc, Cambridge, MA, United States
Dana Farber Cancer Institute, Boston, MA, United States
* Corresponding author; email: kbhalla{at}mcg.edu.
Histone deacetylase (HDAC) 6 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, e.g., BCR-ABL, AKT and c-Raf. In this study, we determined the effect of hsp90 hyperacetylation on the anti-hsp90 and anti-leukemia 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 co-chaperone 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. Co-treatment 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. Additionally, co-treatment with 17-AAG and tubacin augmented the loss of survival of K562 cells and viability of primary AML and CML samples. These findings demonstrate that HDAC6 is an hsp90 client protein and hyperacetylation of hsp90 augments the anti-hsp90 and anti-leukemia effects of 17-AAG.
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