Poster (Scientific congresses and symposiums)Glucose-dependent metabolic reprogramming in HDAC5-depleted cancer cells
Hendrick, Elodie; Peixoto, Paul; Polese, Catherine et al.
2014 • Reactive Oxygen Species in Cell Metabolism 11th Meeting of the FRS-FNRS contact group on oxidative stress and anti-oxidants 210th Meeting of the Belgian Society of Biochemistry and Molecular Biology
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Abstract :
[en] 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 survival (PEIXOTO et al., 2012).
The goal of this study is to further understand the molecular mechanisms of action of HDAC5 in cancer cells.
Screening transcriptomic study demonstrated that HDAC5 depletion induces a down-regulation of subunits of the complex I of the mitochondrial respiratory chain (NDUFB5-NDUFA3) as well as anti-oxydant proteins (Ferritin, Metalothionein,¿) through modulation of mRNA stability. Therefore, HDAC5 depletion causes a significant increase of ROS production inducing both apoptosis and mechanisms of mitochondria quality control (mitophagy and mitobiogenesis). This HDAC5 depletion-induced mitochondrial dysfunction provokes metabolic adaptation associated with increased importance of glycolysis and 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.
Our study demonstrated for the first time that specific HDAC5 inhibition induces metabolic reprogramming and provides insight into a valuable experimental strategy for manipulation of specific HDAC5 inhibition and glucose metabolism in therapy against cancer.
Acknowledgements
This work fiancially suppoted by a grant of F.R.S .-FNRS (contract n° 7.4515.12F). E Hendrick is recipient of a Televie fellowship.
References
PEIXOTO et al., (2012) Cell Death and Differentiation. 7:1239-52.
