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Autophagy. 2012 Oct;8(10):1521-2. doi: 10.4161/auto.21151. Epub 2012 Aug 16.

Curbing autophagy and histone deacetylases to kill cancer cells.

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

Abstract

Cells respond to cytotoxicity by activating a variety of signal transduction pathways. One pathway frequently upregulated during cytotoxic response is macroautophagy (hereafter referred to as autophagy). Previously, we demonstrated that pan-histone deacetylase (HDAC) inhibitors, such as the anticancer agent suberoylanilide hydroxamic acid (SAHA, Vorinostat), can induce autophagy. In this study, we show that HDAC inhibition triggers autophagy by suppressing MTOR and activating the autophagic kinase ULK1. Furthermore, autophagy inhibition can sensitize cells to both apoptotic and nonapoptotic cell death induced by SAHA, suggesting the therapeutic potential of autophagy targeting in combination with SAHA therapy. This study also raised a series of questions: What is the role of HDACs in regulating autophagy? Do individual HDACs have distinct functions in autophagy? How do HDACs regulate the nutrient-sensing kinase MTOR? Since SAHA-induced nonapoptotic cell death is not driven by autophagy, what then is the mechanism underlying the apoptosis-independent death? Tackling these questions should lead to a better understanding of autophagy and HDAC biology and contribute to the development of novel therapeutic strategies.

PMID:
22894919
PMCID:
PMC3973656
DOI:
10.4161/auto.21151
[PubMed - indexed for MEDLINE]
Free PMC Article
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