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Curbing autophagy and histone deacetylases to kill cancer cells

Noor Gammoh1, Paul A Marks, Xuejun Jiang

  • 1Cell Biology Department, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Autophagy
|August 17, 2012
PubMed

Insights

Histone deacetylase (HDAC) inhibitors like SAHA induce autophagy by suppressing MTOR and activating ULK1. Combining autophagy inhibition with SAHA therapy may enhance cancer treatment by sensitizing cells to death.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • Cells activate signal transduction pathways in response to cytotoxicity.
  • Macroautophagy (autophagy) is upregulated during cytotoxic responses.
  • Pan-histone deacetylase (HDAC) inhibitors, including SAHA (Vorinostat), can induce autophagy.

Purpose of the Study:

  • To investigate the mechanism by which HDAC inhibition triggers autophagy.
  • To explore the role of autophagy inhibition in sensitizing cells to SAHA-induced cell death.
  • To identify potential therapeutic strategies combining HDAC inhibitors and autophagy targeting.

Main Methods:

  • Utilized pan-histone deacetylase (HDAC) inhibitors, specifically SAHA (Vorinostat).
  • Investigated the effects of HDAC inhibition on MTOR and ULK1 activation.
  • Assessed the impact of autophagy inhibition on SAHA-induced apoptotic and nonapoptotic cell death.

Main Results:

  • HDAC inhibition was shown to trigger autophagy by suppressing MTOR and activating the autophagic kinase ULK1.
  • Inhibition of autophagy sensitized cells to both apoptotic and nonapoptotic cell death induced by SAHA.
  • The study identified potential therapeutic avenues for combined cancer treatment strategies.

Conclusions:

  • HDAC inhibition is a key regulator of autophagy through the MTOR/ULK1 pathway.
  • Autophagy inhibition represents a promising strategy to enhance the efficacy of SAHA therapy.
  • Further research is needed to elucidate the precise roles of individual HDACs and the mechanisms of SAHA-induced apoptosis-independent cell death.

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