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  • Original Article
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Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition

Abstract

The US FDA approval of broad-spectrum histone deacetylase (HDAC) inhibitors has firmly laid the cancer community to explore HDAC inhibition as a therapeutic approach for cancer treatment. Hitting one HDAC member could yield clinical benefit but this required a complete understanding of the functions of the different HDAC members. Here we explored the consequences of specific HDAC5 inhibition in cancer cells. We demonstrated that HDAC5 inhibition induces an iron-dependent reactive oxygen species (ROS) production, ultimately leading to apoptotic cell death as well as mechanisms of mitochondria quality control (mitophagy and mitobiogenesis). Interestingly, adaptation of HDAC5-depleted cells to oxidative stress passes through reprogramming of metabolic pathways towards glucose and glutamine. Therefore, interference with both glucose and glutamine supply in HDAC5-inhibited cancer cells significantly increases apoptotic cell death and reduces tumour growth in vivo; providing insight into a valuable clinical strategy combining the selective inhibition of HDAC5 with various inhibitors of metabolism as a new therapy to kill cancer cells.

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Acknowledgements

The authors thank the GIGA ‘Cell Imaging and Flow Cytometry’, the GIGA ‘Transciptomic ‘ as well as the GIGA ‘Animal’ core facility for technical assistance. This work was supported by grants from the National Fund for Scientific Research (FNRS) (Belgium), TELEVIE, the Centre Anti-Cancéreux, Fonds Léon Frédéricq and Fonds Spéciaux de Recherche près de l’Université de Liège. PP and JC are FNRS-TELEVIE Post Doc. DM is a Research Associate. P DT is Senior Research Associate and LB is Research Director at the National Fund for Scientific Research (FNRS). CP, EH and AB are FNRS-TELEVIE fellows. NM is FRIA fellow.

Author contributions

Conception and design: E Hendrick, P Peixoto, A Blomme, D Mottet; Development of methodology: E Hendrick, P Peixoto, A Blomme, A Mouithys-Mickalad, D Serteyn, L Bettendorff, B Elmoualij, P De Tullio, G Eppe; Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc): E Hendrick, P Peixoto, A Blomme, N Matheus, C Polese, J Cimino, A Frère, A Mouithys-Mickalad, P De Tullio, D Mottet; Analysis and interpretation of data (for example, statistical analysis, biostatistics, computational analysis): E Hendrick, P Peixoto, A Blomme, N Matheus, J Cimino, A Mouithys-Mickalad, P De Tullio, G Eppe, F Dequiedt, D Mottet; Writing, review, and/or revision of the manuscript: E Hendrick, P Peixoto, A Blomme, F Dequiedt, V Castronovo, D Mottet; Administrative, technical, or material support (that is, reporting or organizing data, constructing databases): E Hendrick, P Peixoto, A Blomme, N Matheus, C Polese, J Cimino, A Frère, G Eppe, D Mottet; Study supervision: E Hendrick, P Peixoto, V Castronovo, D Mottet.

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Correspondence to D Mottet.

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Hendrick, E., Peixoto, P., Blomme, A. et al. Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition. Oncogene 36, 4859–4874 (2017). https://doi.org/10.1038/onc.2017.103

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