Genetic dissection of histone deacetylase requirement in tumor cells.
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.
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Michael
M
Haberland
Aaron
A
Johnson
Mayssa H
MH
Mokalled
Rusty L
RL
Montgomery
Eric N
EN
Olson
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008957:Models, Genetic; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D020033:Protein Isoforms
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D020033:Protein Isoforms; D006655:Histone Deacetylases