Cellular chaperones promote the folding and maturation of newly synthesized 
proteins and partially folded proteins in the cytosol and endoplasmic reticulum 
(ER) as well as prevent the aggregation of misfolded proteins. Histone 
deacetylases (HDACs) and histone acetyl transferases catalyze the reversible 
acetylation of histones and nonhistone substrates to control the epigenetic and 
transcriptomic landscape of normal and tumor cells. Treatment with HDAC 
inhibitors results in the hyperacetylation of chaperones including heat shock 
protein (hsp)90, hsp70, hsp40, and the ER-resident hsp70 homolog, 
glucose-regulated protein 78 (GRP78), which affects their function. HDAC 
inhibitor-mediated deregulation of chaperone function, in turn, deregulates 
protein homeostasis and induces protein misfolding and proteotoxic stress. In 
the context of tumors which are particularly dependent on functional chaperones 
for maintaining protein homeostasis, HDAC inhibitors tip the balance toward 
lethal proteotoxic and ER stress. In this chapter, we describe HDAC 
inhibitor-induced hyperacetylation of major chaperones and its implication for 
the use of HDAC inhibitors in the treatment of solid and hematologic tumors.