Article (Scientific journals)
HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells
Peixoto, Paul; Castronovo, Vincenzo; Matheus, Nicolas et al.
2012In Cell Death and Differentiation
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Keywords :
histone deacetylase; cancer cells; siRNA; autophagy; cell proliferation; chemotherapy
Abstract :
[en] Histone deacetylases (HDACs) form a family of enzymes, which have fundamental roles in the epigenetic regulation of gene expression and contribute to the growth, differentiation, and apoptosis of cancer cells. In this study, we further investigated the biological function of HDAC5 in cancer cells. We found HDAC5 is associated with actively replicating pericentric heterochromatin during late S phase. We demonstrated that specific depletion of HDAC5 by RNA interference resulted in profound changes in the heterochromatin structure and slowed down ongoing replication forks. This defect in heterochromatin maintenance and assembly are sensed by DNA damage checkpoint pathways, which triggered cancer cells to autophagy and apoptosis, and arrested their growth both in vitro and in vivo. Finally, we also demonstrated that HDAC5 depletion led to enhanced sensitivity of DNA to DNA-damaging agents, suggesting that heterochromatin de-condensation induced by histone HDAC5 silencing may enhance the efficacy of cytotoxic agents that act by targeting DNA in vitro. Together, these results highlighted for the first time an unrecognized link between HDAC5 and the maintenance/assembly of heterochromatin structure, and demonstrated that its specific inhibition might contribute to increase the efficacy of DNA alteration-based cancer therapies in clinic.
Research center :
Giga-Cancer - ULiège
Disciplines :
Oncology
Author, co-author :
Peixoto, Paul ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
Castronovo, Vincenzo ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire
Matheus, Nicolas ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
Polese, Catherine ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire
Peulen, Olivier  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Gonzalez, Arnaud ;  Université de Liège - ULiège > Form. doc. sc. bioméd. & pharma.
Boxus, Mathieu ;  Université de Liège - ULiège > Chimie et bio-industries > Biologie cell. et moléc.
Verdin, Eric;  University of California, San Francisco > Gladstone Institute of Virology and Immunology
Thiry, Marc  ;  Université de Liège - ULiège > Département des sciences de la vie > Biologie cellulaire
Dequiedt, Franck  ;  Université de Liège - ULiège > GIGA-Research
Mottet, Denis ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
Language :
English
Title :
HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells
Publication date :
2012
Journal title :
Cell Death and Differentiation
ISSN :
1350-9047
eISSN :
1476-5403
Publisher :
Nature Publishing Group, London, United Kingdom
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
CAC - Centre anticancéreux près l'Université de Liège asbl [BE]
Fonds Léon Fredericq [BE]
Télévie [BE]
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