title: HDAC inhibitors and chaperone function.
abstract: 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.
authors.affiliation: The University of Kansas Cancer Center, Kansas City, Kansas, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Rao
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Ganguly
authors.forename: Suman
authors.initials: S
authors.lastname: Kambhampati
authors.forename: Kapil N
authors.initials: KN
authors.lastname: Bhalla
mesh_terms: D000107:Acetylation; D000818:Animals; D000091342:Endoplasmic Reticulum Chaperone BiP; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D056572:Histone Deacetylase Inhibitors; D018832:Molecular Chaperones; D006655:Histone Deacetylases