Curbing autophagy and histone deacetylases to kill cancer cells
Volume 8, Issue 10
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Pages 1521 - 1522http://dx.doi.org/10.4161/auto.21151
: HDAC inhibitors, MTOR, SAHA, ULK1, apoptosis, autophagy, nonapoptotic cell death
Authors: Noor Gammoh, Paul A. Marks and Xuejun Jiang View affiliations
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.
Autophagic Punctum to:
N Gammoh, D Lam, C Puente, I Ganley, PA Marks, X Jiang. Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. Proc Natl Acad Sci U S A 2012; 109: 6561-5
PMID: 22493260 DOI: 10.1073/pnas.1204429109
Received: June 1, 2012; Accepted: June 18, 2012; Published Online: August 16, 2012
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