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Complex I Mitochondrial Dysfunction in HDAC5-depleted Cancer Cells Induces Glucose-dependent Metabolic Reprogramming
Hendrick, Elodie; Peixoto, Paul; Matheus, Nicolas et al.
2014Giga Day 2014
 

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Keywords :
HDAC5; Metabolism; Cancer
Abstract :
[en] Introduction : Histone deacetylases (HDAC) is a family of eighteen enzymes, which modulates the acetylation level of histones and non-histone proteins to regulate gene expression and chromatin structure. Broad-spectrum inhibitors of these enzymes such as SAHA can inhibit tumor growth both in vitro and in vivo and are currently used as anti-cancer agents in clinic. For many years, we are investigating the specific role of individual HDAC members in cancer biology and we have recently demonstrated that specific depletion of HDAC5 using siRNA technology reduced cancer cells proliferation and survival1. Aims : The goal of this study is to further understand the molecular mechanisms of action of HDAC5 in cancer cells. Methods and results : Screening transcriptomic study demonstrated that HDAC5 depletion induces a down-regulation of NDUFB5, a subunit of the complex I of the mitochondrial respiratory chain through modulation of mRNA stability. HDAC5 depletion-induced NDUFB5 downregulation causes a significant increase of ROS production and induces uncoupled mitochondrial respiration. In addition, this HDAC5 depletion-induced mitochondrial dysfunction provokes metabolic adaptation associated with increased importance of glucose. Indeed, interference with glucose supply in HDAC5-depleted cancer cells significantly increases apoptotic cell death suggesting that glucose deprivation might be combined to HDAC5 inhibition as a therapeutic strategy to kill cancer cells. Conclusions : Our study demonstrated for the first time that specific HDAC5 inhibition induces alteration of NDUFB5 gene expression by altering mRNA stability and provides insight into a valuable experimental strategy for manipulation of specific HDAC5 inhibition and glucose metabolism in therapy against cancer. 1.Peixoto, P. et al. HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells. Cell death and differentiation, 2012; 1-14.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Hendrick, Elodie ;  Université de Liège > Département des sciences de la vie > Génétique et biologie moléculaires animales
Peixoto, Paul ;  Université de Liège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
Matheus, Nicolas ;  Université de Liège - ULiège > Form. doc. sc. bioméd. & pharma.
Polese, Catherine ;  Université de Liège - ULiège > Form. doc. sc. bioméd. & pharma.
Blomme, Arnaud  ;  Université de Liège - ULiège > Doct. sc. bioméd. & pharma. (Bologne)
Mouithys-Mickalad, Ange ;  Université de Liège > Centre de l'oxygène : Recherche et développement (C.O.R.D.)
Serteyn, Didier  ;  Université de Liège > Dép. clinique des animaux de compagnie et des équidés (DCA) > Anesthésiologie gén. et pathologie chirurg. des grds animaux
De Tullio, Pascal ;  Université de Liège > Département de pharmacie > Chimie pharmaceutique
Elmoualij, Benaïssa ;  Université de Liège > Département des sciences biomédicales et précliniques > Histologie
Sonveaux, Pierre
Castronovo, Vincenzo ;  Université de Liège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire
Mottet, Denis  ;  Université de Liège > Département des sciences de la vie > Génétique et biologie moléculaires animales
Language :
English
Title :
Complex I Mitochondrial Dysfunction in HDAC5-depleted Cancer Cells Induces Glucose-dependent Metabolic Reprogramming
Publication date :
27 January 2014
Number of pages :
A0
Event name :
Giga Day 2014
Event place :
Liège, Belgium
Event date :
Du 27 janvier 2014 au 27 janvier 2014
By request :
Yes
Available on ORBi :
since 03 June 2015

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