Mitochondrial dysfunction in HDAC5-depleted cancer cells induces glucose-dependent metabolic adaptation

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 depletion of HDAC5 using siRNA technology triggered cancer cells to both autophagy and apoptosis1. Aims: The goal of this study is to further investigate the molecular mechanisms by which HDAC5 depletion induces both autophagy and apoptosis in cancer cells. 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. This ROS accumulation promotes autophagy including mitophagy. Indeed, pretreatment with NAC, a ROS scavenger, blocked autophagy triggered by HDAC5 silencing. This autophagy seems to be protective as its blocking with NAC, chloroquine or bafilomycin A1 enhances pro-apoptotic effect of HDAC5 depletion. In addition, mitochondrial dysfunction provokes metabolism adaptation associated with increase of the importance of glucose metabolism in HDAC5 depleted cancer cells. Indeed, low-glucose culture of HDAC5-depleted 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