title: Targeting histone deacetylase 8 as a therapeutic approach to cancer and neurodegenerative diseases.
abstract: Histone deacetylase 8 (HDAC8), a unique class I zinc-dependent HDAC, is an emerging target in cancer and other diseases. Its substrate repertoire extends beyond histones to many nonhistone proteins. Besides being a deacetylase, HDAC8 also mediates signaling via scaffolding functions. Aberrant expression or deregulated interactions with transcription factors are critical in HDAC8-dependent cancers. Many potent HDAC8-selective inhibitors with cellular activity and anticancer effects have been reported. We present HDAC8 as a druggable target and discuss inhibitors of different chemical scaffolds with cellular effects. Furthermore, we review HDAC8 activators that revert activity of mutant enzymes. Isotype-selective HDAC8 targeting in patients with HDAC8-relevant cancers is challenging, however, is promising to avoid adverse side effects as observed with pan-HDAC inhibitors.
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
authors: Alokta
authors: A
authors: Chakrabarti
authors: Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
authors: Jelena
authors: J
authors: Melesina
authors: Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors: Fiona R
authors: FR
authors: Kolbinger
authors: Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors: Ina
authors: I
authors: Oehme
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
authors: Johanna
authors: J
authors: Senger
authors: Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.|Department of Pediatric Oncology, Hematology & Immunology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Olaf
authors: O
authors: Witt
authors: Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
authors: Wolfgang
authors: W
authors: Sippl
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.|German Cancer Consortium (DKTK), Freiburg, Germany.
authors: Manfred
authors: M
authors: Jung
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases
keywords: HDAC8; SMC3; T-cell; cancer; druggable; hydroxamic acid; inhibitor; stem cell; therapy