Review
Drugging the HDAC6–HSP90 interplay in malignant cells

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Highlights

  • HDAC6 has unique cytoprotective functions.

  • HDAC6 is a valid target for pharmacological intervention strategies.

  • The HDAC6–HSP90 interplay is more complex and important than anticipated.

  • An increasing number of PTMs controls HDAC6 and HSP90.

  • Certain structures determine the specificity of drugs against HDAC6.

  • Future development of increasingly selective and potent HDAC6i is anticipated.

Acetylation and deacetylation cycles regulate crucial biological processes. The enzymes deacetylating lysine residues are termed histone deacetylases (HDACs). Eighteen deacetylases have been isolated from mammalian cells. There is an intense search underway for individual functions of these enzymes and for selective histone deacetylase inhibitors (HDACi). HDAC6 in particular has unique cytoprotective functions that rely on its ability to ensure protein homeostasis and to prevent protein aggregation. The chaperone heat shock protein 90 (HSP90) also safeguards proteins and is deacetylated by HDAC6. Current data illustrate the complexity and importance of the HDAC6–HSP90 interplay. In this review, we discuss how recently identified HSP90-dependent regulators of posttranslational modifications (PTMs) of HDAC6 dictate its functions, and how HDACi-induced acetylation of HSP90 might control oncologically relevant proteins, especially in leukemic cells. Additionally, we discuss small molecules blocking HDAC6 and how such agents could become therapeutically relevant. We summarize structure–function relationships that determine the specificity of drugs against HDAC6.

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.

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