title: A regulatory circuit that involves HR23B and HDAC6 governs the biological response to HDAC inhibitors.
abstract: Histone deacetylase (HDAC) is an emergent anticancer target, and HR23B is a biomarker for response to HDAC inhibitors. We show here that HR23B has impacts on two documented effects of HDAC inhibitors; HDAC inhibitors cause apoptosis in cells expressing high levels of HR23B, whereas in cells with low level expression, HDAC inhibitor treatment is frequently associated with autophagy. The mechanism responsible involves the interaction of HDAC6 with HR23B, which downregulates HR23B and thereby reduces the level of ubiquitinated substrates targeted to the proteasome, ultimately desensitising cells to apoptosis. Significantly, the ability of HDAC6 to downregulate HR23B occurs independently of its deacetylase activity. An analysis of the HDAC6 interactome identified HSP90 as a key effector of HDAC6 on HR23B levels. Our results define a regulatory mechanism that involves the interplay between HR23B and HDAC6 that influences the biological outcome of HDAC inhibitor treatment.
authors.affiliation: Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Old Road Campus, off Roosevelt Drive, Headington, Oxford, UK
authors.forename: M
authors.initials: M
authors.lastname: New
authors.forename: H
authors.initials: H
authors.lastname: Olzscha
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.forename: O
authors.initials: O
authors.lastname: Khan
authors.forename: L
authors.initials: L
authors.lastname: Stimson
authors.forename: J
authors.initials: J
authors.lastname: McGouran
authors.forename: D
authors.initials: D
authors.lastname: Kerr
authors.forename: A
authors.initials: A
authors.lastname: Coutts
authors.forename: B
authors.initials: B
authors.lastname: Kessler
authors.forename: M
authors.initials: M
authors.lastname: Middleton
authors.forename: N B
authors.initials: NB
authors.lastname: La Thangue
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; C513287:RAD23B protein, human; D034741:RNA, Small Interfering; D025801:Ubiquitin; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D045643:DNA Repair Enzymes