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Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition

E Hendrick1, P Peixoto2, A Blomme2

  • 1University of Liege, GIGA-Molecular Biology of Diseases, Protein Signalisation and Interaction (PSI) Laboratory, Liège, Belgium.

Oncogene
|April 18, 2017
PubMed

Insights

Selective HDAC5 inhibition triggers cancer cell death via iron-dependent ROS production and metabolic reprogramming. Combining HDAC5 inhibitors with metabolic blockers enhances apoptosis and reduces tumor growth, offering a novel cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Histone deacetylase (HDAC) inhibitors are investigated for cancer therapy.
  • Understanding individual HDAC member functions is crucial for targeted treatment.
  • Specific inhibition of HDAC5 in cancer cells was explored.

Purpose of the Study:

  • To investigate the effects of HDAC5 inhibition in cancer cells.
  • To identify mechanisms driving cancer cell death upon HDAC5 inhibition.
  • To explore potential therapeutic strategies combining HDAC5 inhibition with metabolic targeting.

Main Methods:

  • Inhibition of HDAC5 in cancer cell lines.
  • Assessment of reactive oxygen species (ROS) production.
  • Analysis of mitochondrial quality control pathways (mitophagy, mitobiogenesis).
  • Metabolic pathway analysis under oxidative stress.
  • In vivo tumor growth studies.

Main Results:

  • HDAC5 inhibition induces iron-dependent ROS production, leading to apoptosis.
  • HDAC5 inhibition affects mitophagy and mitobiogenesis.
  • Cancer cells adapt to oxidative stress by reprogramming metabolism towards glucose and glutamine.
  • Combined inhibition of HDAC5 and metabolic pathways (glucose/glutamine) increases apoptosis and reduces tumor growth in vivo.

Conclusions:

  • HDAC5 inhibition is a potential anti-cancer strategy.
  • Targeting both HDAC5 and cancer cell metabolism offers a promising therapeutic approach.
  • This combination therapy enhances cancer cell death and inhibits tumor progression.

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