A regulatory circuit that involves HR23B and HDAC6 governs the biological response to HDAC inhibitors.
Cell Death Differ
; 20(10): 1306-16, 2013 Oct.
Article
em En
| MEDLINE
| ID: mdl-23703321
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Apoptose
/
Ubiquitina
/
Enzimas Reparadoras do DNA
/
Proteínas de Ligação a DNA
/
Inibidores de Histona Desacetilases
/
Histona Desacetilases
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Cell Death Differ
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Reino Unido