Trends in Pharmacological Sciences
ReviewDrugging the HDAC6–HSP90 interplay in malignant cells
Section snippets
HDAC6 has distinct molecular features and functions
HDACs shape cellular signaling and gene expression via the removal of acetyl groups attached to lysine residues in histones and non-histone proteins 1, 2. HDACs are frequently dysregulated in tumors and contribute to a loss of cell cycle control, differentiation, and apoptosis 3, 4. Therefore, HDACs are valid pharmacological targets. In this review, we summarize how the interplay between HSP90 and HDAC6 affects the fate of transformed cells, and we discuss how HDAC6 can be inhibited with low
Expression of HDAC6 in hematologic malignancies
A comparison of HDAC6 mRNA levels in healthy human peripheral blood progenitor cells with AML cell lines and 23 primary AML blasts demonstrated that AML blasts show higher HDAC6 levels [21]. A study analyzing mRNAs from 200 chronic lymphatic leukemia (CLL) patients found that HDAC6 was increased in CLL B cells when compared with peripheral and umbilical cord B cells. Nonetheless, high HDAC6 expression turned out to be a marker for treatment-free survival and better prognosis [22]. A comparison
Structure of HDACi and achievement of specificity for HDAC6
HDACi have three functional groups (Figure 2). Chemical modification of the cap group allowed the generation of isoform-selective HDACi. Tubastatin-A was developed on a structure-based design combined with homology modeling [14]. The dimensions of the catalytic channel rim differ significant between HDACs. Tubastatin-A's tricyclic cap group is large and rigid enough to occupy the wider channel rim in the catalytic domain of HDAC6, DD2Gly482-Gly801. Combination with a tolyl linker, N-bonded
Interplay between HDAC6 and HSP90 at the level of PTMs
Links between HDAC6 and HSP90 can also be mediated by PTMs and the enzymes catalyzing them. Cancer-relevant EGFR–RAS–RAF–MEK–ERK signaling induces phosphorylation of HDAC6 at Ser1035 and deacetylation of α-tubulin [36] (Table 2). HDACi block this pathway, and this correlates with HSP90 acetylation in leukemic cells and in lung cancer cells 34, 37. The HA pan-HDACi LBH589 reduces ERK1/2 activation in AML and CML cells 37, 38, indicating that HDAC6 can be targeted directly and indirectly. It
Interaction between HDAC6–HSP90 as drug target in leukemic cells
HSP90 aids the folding and stability of LFPs (BCR-ABL, AML1-ETO, PML-RARα), of mutant FLT3, c-KIT, AKT, c-RAF, of the pan-leukemic marker protein WT1, and of p53 mutants 6, 7, 20, 37, 50. HDAC6-mediated deacetylation of HSP90 was reported as a prerequisite to bind and protect these oncoproteins from proteasomal degradation [51].
Studies conducted with leukemic cells suggested that HDAC6 regulated HSP90 acetylation and thereby the proteasomal degradation of BCR-ABL and FLT3-ITD. Furthermore,
Concluding remarks
Although it was tempting to postulate a linear relationship between HSP90 deacetylation and oncoprotein stability, accumulating evidence suggests a more complicated scenario and the initial conclusions require re-assessment. The link between the destabilization of leukemogenic proteins and HSP90 acetylation comprises a large number of acetylated lysine moieties in HSP90 and their putative crosstalk. Whether inhibiting HDAC6 and thereby HSP90 at a certain stage of transformation can prevent
Acknowledgments
We apologize to all authors whose work was not cited due to space limitations or an oversight on our part. Work in our groups is supported by the Deutsche Forschungsgemeinschaft (KR 2291/4-1/MA 2183/1-1), the German Cancer Aid (#110909 and #110125), the Wilhelm Sander-Stiftung (#2010.078.2), and intramural fundings.
References (67)
Histone/protein deacetylases control Foxp3 expression and the heat shock response of T-regulatory cells
Curr. Opin. Immunol.
(2011)Exploiting epigenetic vulnerabilities for cancer therapeutics
Trends Pharmacol. Sci.
(2014)HDAC2: a critical factor in health and disease
Trends Pharmacol. Sci.
(2009)Development and therapeutic impact of HDAC6-selective inhibitors
Biochem. Pharmacol.
(2012)Modulation of histone deacetylase 6 (HDAC6) nuclear import and tubulin deacetylase activity through acetylation
J. Biol. Chem.
(2012)LC3B-II deacetylation by histone deacetylase 6 is involved in serum-starvation-induced autophagic degradation
Biochem. Biophys. Res. Commun.
(2013)Inhibition of HDAC6 deacetylase activity increases its binding with microtubules and suppresses microtubule dynamic instability in MCF-7 cells
J. Biol. Chem.
(2013)Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors
Blood
(2012)Cell transformation by FLT3 ITD in acute myeloid leukemia involves oxidative inactivation of the tumor suppressor protein-tyrosine phosphatase DEP-1/PTPRJ
Blood
(2012)A novel small molecule deubiquitinase inhibitor blocks Jak2 signaling through Jak2 ubiquitination
Cell. Signal.
(2011)
Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells
Blood
HDAC6 as a target for antileukemic drugs in acute myeloid leukemia
Leuk. Res.
Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma
Blood
Tubulin polymerization promoting protein 1 (Tppp1) phosphorylation by Rho-associated coiled-coil kinase (rock) and cyclin-dependent kinase 1 (Cdk1) inhibits microtubule dynamics to increase cell proliferation
J. Biol. Chem.
Post-translational modifications of Hsp90 and their contributions to chaperone regulation
Biochim. Biophys. Acta
A prescription for ‘stress’ – the role of Hsp90 in genome stability and cellular adaptation
Trends Cell Biol.
Extracellular signal-regulated kinase (ERK) phosphorylates histone deacetylase 6 (HDAC6) at serine 1035 to stimulate cell migration
J. Biol. Chem.
HDAC6 inhibition enhances 17-AAG–mediated abrogation of hsp90 chaperone function in human leukemia cells
Blood
Pan-histone deacetylase inhibitor panobinostat depletes CXCR4 levels and signaling and exerts synergistic antimyeloid activity in combination with CXCR4 antagonists
Blood
Regulation of CD133 by HDAC6 promotes beta-catenin signaling to suppress cancer cell differentiation
Cell Rep.
Anti-proliferative activity of heat shock protein (Hsp) 90 inhibitors via beta-catenin/TCF7L2 pathway in adult T cell leukemia cells
Cancer Lett.
Tubulin polymerization promoting protein 1 (TPPP1) increases beta-catenin expression through inhibition of HDAC6 activity in U2OS osteosarcoma cells
Biochem. Biophys. Res. Commun.
Novel players in multiple myeloma pathogenesis: role of protein kinases CK2 and GSK3
Leuk. Res.
Acetylation of histone deacetylase 6 by p300 attenuates its deacetylase activity
Biochem. Biophys. Res. Commun.
MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells
Leuk. Res.
AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated Kit
Blood
FK228 inhibits Hsp90 chaperone function in K562 cells via hyperacetylation of Hsp70
Biochem. Biophys. Res. Commun.
Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor-resistant acute myeloid leukemia cells
Blood
An acetylation site in the middle domain of Hsp90 regulates chaperone function
Mol. Cell
4,5,6,7-Tetrahydro-isoxazolo-[4,5-c]-pyridines as a new class of cytotoxic Hsp90 inhibitors
Eur. J. Med. Chem.
Hallmarks of cancer: the next generation
Cell
Erasers of histone acetylation: the histone deacetylase enzymes
Cold Spring Harb. Perspect. Biol.
Inhibitors of HDACs – effective drugs against cancer?
Curr. Cancer Drug Targets
Cited by (109)
Development of a tetrahydroindazolone-based HDAC6 inhibitor with in-vivo anti-arthritic activity
2024, Bioorganic and Medicinal ChemistryButein inhibits cancer cell growth by rescuing the wild-type thermal stability of mutant p53
2023, Biomedicine and PharmacotherapyTargeting the lncMST-EPRS/HSP90AB1 complex as novel therapeutic strategy for T-2 toxin-induced growth retardation
2022, Ecotoxicology and Environmental SafetyDesign, synthesis, and biological evalution of bifunctional inhibitors against Hsp90-HDAC6 interplay
2022, European Journal of Medicinal ChemistryHeat shock protein 90 (Hsp90)/Histone deacetylase (HDAC) dual inhibitors for the treatment of azoles-resistant Candida albicans
2022, European Journal of Medicinal Chemistry