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Inhibition of Histone Deacetylase 6 Acetylates and Disrupts the Chaperone Function of Heat Shock Protein 90
Open accessAbstract
The hydroxamic acid (HAA) analogue pan-histone deacetylase (HDAC) inhibitors (HDIs) LAQ824 and LBH589 have been shown to induce acetylation and inhibit the ATP binding and chaperone function of heat shock protein (HSP) 90. This promotes the polyubiquitylation and degradation of the pro-growth and pro-survival client proteins Bcr-Abl, mutant FLT-3, c-Raf, and AKT in human leukemia cells. HDAC6 is a member of the class IIB HDACs. It is predominantly cytosolic, microtubule-associated alpha-tubulin deacetylase that is also known to promote aggresome inclusion of the misfolded polyubiquitylated proteins. Here we demonstrate that in the Bcr-abl oncogene expressing human leukemia K562 cells, HDAC6 can be co-immunoprecipitated with HSP90, and the knock-down of HDAC6 by its siRNA induced the acetylation of HSP90 and alpha-tubulin. Depletion of HDAC6 levels also inhibited the binding of HSP90 to ATP, reduced the chaperone association of HSP90 with its client proteins, e.g. Bcr-Abl, and induced polyubiquitylation and partial depletion of Bcr-Abl. Conversely, the ectopic overexpression of HDAC6 inhibited LAQ824-induced acetylation of HSP90 and alpha-tubulin and reduced LAQ824-mediated depletion of Bcr-Abl, AKT, and c-Raf. Collectively, these findings indicate that HDAC6 is also an HSP90 deacetylase. Targeted inhibition of HDAC6 leads to acetylation of HSP90 and disruption of its chaperone function, resulting in polyubiquitylation and depletion of pro-growth and pro-survival HSP90 client proteins including Bcr-Abl. Depletion of HDAC6 sensitized human leukemia cells to HAA-HDIs and proteasome inhibitors.
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In the citing paper
“To further investigate the potential of acetylation to inhibit Hsp90 function, we used trichostatin A (TSA), which was shown to induce acetylation of Hsp90 in eukaryotes (17–20).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [17]
In the citing paper
“HDAC6 was shown to be the deacetylase for a diverse set of substrates involved in tumourigenesis, such as HSP90, α-tubulin, cortactin and peroxiredoxins”
From A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth (2013) · cites this paper as Bali et al, 2005
In the citing paper
“HDAC6 knockout in mice does not lead to embryonic lethality”
From A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth (2013) · cites this paper as Bali et al, 2005
In the citing paper
“unlike other HDACs, inhibition of HDAC6 is believed not to be associated with severe toxicity”
From A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth (2013) · cites this paper as Bali et al, 2005
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Research works printed but not linked: 5
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- Nimmanapalli, 2003, Cancer Res., 63, 5126
- Fuino, 2003, Mol. Cancer Ther., 2, 971
- Nimmanapalli, 2002, Cancer Res., 62, 5761
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Metadata
- Authors
- Bali, P., Pranpat, M., Bradner, J., Balasis, M., Fiskus, W., Guo, F., Rocha, K., Kumaraswamy, S., Boyapalle, S., Atadja, P., Seto, E., & Bhalla, K.
- Affiliations
- Moffitt Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- Novartis (United States) (US)
- Corresponding author
- Bhalla, Kapil
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-07
- Volume
- 280
- Issue
- 29
- Pages
- 26729-26734
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2151445954
- Cited by
- 755
- References
- 42
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 10 · 2023: 9 · 2022: 23 · 2021: 21 · 2020: 38 · 2019: 33 · 2018: 32 · 2017: 28 · 2016: 34 · 2015: 40 · 2014: 45 · 2013: 42 · 2012: 47
- FWCI
- 19.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- HDAC6, HSP90, HSP90 acetylation, LAQ824, panobinostat, BCR-ABL, alpha-tubulin deacetylation, polyubiquitination, Hsp90 client proteins, Akt, Raf-1, leukemia, K562 cells, proteasome inhibitors, siRNA knockdown
- MeSH terms
- Histone Deacetylase 6, Panobinostat, Acetylation, Antineoplastic Agents, Enzyme Inhibitors, Histone Deacetylases, Humans, Hydroxamic Acids, Indoles, Leukemia, Neoplasm Proteins, Protein Binding, Molecular Chaperones, HSP90 Heat-Shock Proteins, K562 Cells, Ubiquitin, Histone Deacetylase Inhibitors
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