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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 metabolic response of cancer cells to HDAC5 depletion.
Results: Screening transcriptomic study demonstrated that HDAC5 depletion induces a deregulation of genes encoding subunits of complex I of the mitochondrial respiratory chain leading to a significant increase of ROS production and inducing 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.
Conclusion: Our study demonstrated for the first time that specific HDAC5 inhibition induces alteration of gene expression encoding mitochondrial proteins in cancer cells and provide 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.
elodie.hendrick@student.ulg.ac.be
