Apoptotic and autophagic cell death induced by histone deacetylase inhibitors Journal Article


Authors: Shao, Y.; Gao, Z.; Marks, P. A.; Jiang, X.
Article Title: Apoptotic and autophagic cell death induced by histone deacetylase inhibitors
Abstract: Histone deacetylase (HDAC) inhibitors can induce programmed cell death in cancer cells, although the underlying mechanism is obscure. In this study, we show that two distinct HDAC inhibitors, butyrate and suberoylanilide hydroxamic acid (SAHA), induced caspase-3 activation and cell death in multiple human cancer cell lines. The activation of caspase-3 was via the mitochondria/ cytochrome c-mediated apoptotic pathway because it was abrogated in mouse embryonic fibroblasts with knockout of Apaf-1, the essential mediator of the pathway. Overexpression of Bel-XL in HeLa cells also blocked caspase activation by the HDAC inhibitors. Nevertheless, Apaf-1 knockout, overexpression of Bel-XL, and pharmacological inhibition of caspase activity did not prevent SAHA and butyrate-induced cell death. The cells undergoing such caspase-independent death had unambiguous morphological features of autophagic cell death. Therefore, HDAC inhibitors can induce both mitochondria-mediated apoptosis and caspase-independent autophagic cell death. Induction of autophagic cell death by HDAC inhibitors has clear clinical implications in treating cancers with apoptotic defects.
Keywords: controlled study; human cell; histone deacetylase inhibitor; nonhuman; chemotherapy; neoplasms; proteins; animal cell; mouse; animals; mice; mice, knockout; cell death; apoptosis; enzyme inhibition; caspase 3; enzyme activation; dose-response relationship, drug; caspase; protein bcl xl; bcl-x protein; caspases; cell line, tumor; hela cells; time factors; animalia; enzyme inhibitors; cancer cell; vorinostat; hydroxamic acids; fibroblast; fibroblasts; autophagy; mitochondria; histone deacetylases; proto-oncogene proteins c-bcl-2; mitochondrion; subcellular fractions; cytosol; knockout mouse; butyric acid; microscopy, electron, transmission; cytochrome c; cytochromes c; apoptotic protease activating factor 1; apoptotic protease-activating factor 1; butyrates; humans; human; priority journal; article
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 101
Issue: 52
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2004-12-28
Start Page: 18030
End Page: 18035
Language: English
DOI: 10.1073/pnas.0408345102
PROVIDER: scopus
PMCID: PMC539807
PUBMED: 15596714
DOI/URL:
Notes: Proc. Natl. Acad. Sci. U. S. A. -- Cited By (since 1996):306 -- Export Date: 16 June 2014 -- CODEN: PNASA -- Source: Scopus
Altmetric Score
MSK Authors
  1. Xuejun Jiang
    84 Jiang
  2. Zhonghua Gao
    6 Gao
  3. Paul Marks
    149 Marks
  4. Yufang Shao
    7 Shao