title: The therapeutic hope for HDAC6 inhibitors in malignancy and chronic disease.
abstract: Recent years have witnessed an emergence of a new class of therapeutic agents, termed histone deacetylase 6 (HDAC6) inhibitors. HDAC6 is one isoform of a family of HDAC enzymes that catalyse the removal of functional acetyl groups from proteins. It stands out from its cousins in almost exclusively deacetylating cytoplasmic proteins, in exerting deacetylation-independent effects and in the success that has been achieved in developing relatively isoform-specific inhibitors of its enzymatic action that have reached clinical trial. HDAC6 plays a pivotal role in the removal of misfolded proteins and it is this role that has been most successfully targeted to date. HDAC6 inhibitors are being investigated for use in combination with proteasome inhibitors for the treatment of lymphoid malignancies, whereby HDAC6-dependent protein disposal currently limits the cytotoxic effectiveness of the latter. Similarly, numerous recent studies have linked altered HDAC6 activity to the pathogenesis of neurodegenerative diseases that are characterized by misfolded protein accumulation. It seems likely though that the function of HDAC6 is not limited to malignancy and neurodegeneration, the deacetylase being implicated in a number of other cellular processes and diseases including in cardiovascular disease, inflammation, renal fibrosis and cystogenesis. Here, we review the unique features of HDAC6 that make it so appealing as a drug target and its currently understood role in health and disease. Whether HDAC6 inhibition will ultimately find a clinical niche in the treatment of malignancy or prevalent complex chronic diseases remains to be determined.
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada M5C 2T2.
authors.forename: Sri N
authors.initials: SN
authors.lastname: Batchu
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada M5C 2T2.
authors.forename: Angela S
authors.initials: AS
authors.lastname: Brijmohan
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada M5C 2T2 advania@smh.ca.
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
mesh_terms: D002908:Chronic Disease; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D019636:Neurodegenerative Diseases / Q000188:drug therapy*
chemical_list: D056572:Histone Deacetylase Inhibitors; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: aggresome; cancer; histone deacetylase 6 (HDAC6); misfolded protein response; neurodegenerative disease; proteasome