Genetic dissection of histone deacetylase requirement in tumor cells
Open Access
- 12 May 2009
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 106 (19), 7751-7755
- https://doi.org/10.1073/pnas.0903139106
Abstract
Histone deacetylase inhibitors (HDACi) represent a new group of drugs currently being tested in a wide variety of clinical applications. They are especially effective in preclinical models of cancer where they show antiproliferative action in many different types of cancer cells. Recently, the first HDACi was approved for the treatment of cutaneous T cell lymphomas. Most HDACi currently in clinical development act by unspecifically interfering with the enzymatic activity of all class I HDACs (HDAC1, 2, 3, and 8), and it is widely believed that the development of isoform-specific HDACi could lead to better therapeutic efficacy. The contribution of the individual class I HDACs to different disease states, however, has so far not been fully elucidated. Here, we use a genetic approach to dissect the involvement of the different class I HDACs in tumor cells. We show that deletion of a single HDAC is not sufficient to induce cell death, but that HDAC1 and 2 play redundant and essential roles in tumor cell survival. Their deletion leads to nuclear bridging, nuclear fragmentation, and mitotic catastrophe, mirroring the effects of HDACi on cancer cells. These findings suggest that pharmacological inhibition of HDAC1 and 2 may be sufficient for anticancer activity, providing an experimental framework for the development of isoform-specific HDAC inhibitors.Keywords
This publication has 60 references indexed in Scilit:
- The many roles of histone deacetylases in development and physiology: implications for disease and therapyNature Reviews Genetics, 2009
- Isoform-selective histone deacetylase inhibitorsChemical Society Reviews, 2008
- Deletion of Histone Deacetylase 3 Reveals Critical Roles in S Phase Progression and DNA Damage ControlMolecular Cell, 2008
- Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networksThe EMBO Journal, 2008
- The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and menNature Reviews Molecular Cell Biology, 2008
- Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysisThe Lancet Oncology, 2008
- Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomyBritish Journal of Cancer, 2008
- Anticancer activities of histone deacetylase inhibitorsNature Reviews Drug Discovery, 2006
- Histone deacetylase-1 and -3 protein expression in human breast cancer: a tissue microarray analysisBreast Cancer Research and Treatment, 2005
- Upregulation and Nuclear Recruitment of HDAC1 in Hormone Refractory Prostate CancerThe Prostate, 2004