Genetic dissection of histone deacetylase requirement in tumor cells

Michael Haberland, Aaron Johnson, Mayssa H. Mokalled, Rusty L. Montgomery, Eric N. Olson

Research output: Contribution to journalArticle

76 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7751-7755
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number19
DOIs
StatePublished - May 12 2009

Fingerprint

Histone Deacetylase Inhibitors
Histone Deacetylases
Dissection
Neoplasms
Protein Isoforms
Cutaneous T-Cell Lymphoma
Cell Survival
Cell Death
Pharmacology
Pharmaceutical Preparations

Keywords

  • Acetylation
  • Cancer
  • HDAC inhibitor
  • Mitotic catastrophe
  • Tumorigenesis

ASJC Scopus subject areas

  • General

Cite this

Genetic dissection of histone deacetylase requirement in tumor cells. / Haberland, Michael; Johnson, Aaron; Mokalled, Mayssa H.; Montgomery, Rusty L.; Olson, Eric N.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 19, 12.05.2009, p. 7751-7755.

Research output: Contribution to journalArticle

Haberland, Michael ; Johnson, Aaron ; Mokalled, Mayssa H. ; Montgomery, Rusty L. ; Olson, Eric N. / Genetic dissection of histone deacetylase requirement in tumor cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 19. pp. 7751-7755.
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