Drugging the HDAC6–HSP90 interplay in malignant cells

•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.