Histone deacetylase inhibitors induce premature sister chromatid separation and override the mitotic spindle assembly checkpoint.
Histone deacetylase inhibitors (HDACI) are powerful antiproliferative drugs, and are currently undergoing clinical trials as antitumor agents. It would be valuable for both cancer therapy and our knowledge of basic cellular processes to understand the mechanisms by which HDACIs block cell proliferation. Most current models postulate that HDACIs allow the reexpression of tumor suppressor genes silenced in cancer cells. However, other mechanisms, distinct from transcription regulation, may participate in HDACI antiproliferative properties. We report that HDACI treatment induces premature sister chromatid separation in cells in which the mitotic spindle assembly checkpoint (SAC) has already been activated. This effect was transcription-independent. In addition, HDACI-treated mitotic cells displayed SAC inactivation characteristics, including anaphase-promoting complex/cyclosome target degradation, cyclin-dependent kinase 1 inactivation, histone H3 dephosphorylation, and loss of the SAC component MAD2 from the kinetochore. Thus, HDAC inhibition renders the SAC ineffective. Our findings help elucidate the molecular mechanisms of proliferative cell death induced by HDACI treatment and may allow new HDACI-based preclinical and clinical trial protocols to be redesigned so as to target mitosis.
Magnaghi-Jaulin
Laura
L
INSERM EMI 229, CRLC Val d'Aurelle-Paul Lamarque, and Université MONTPELLIER1, Montpellier, France.
Eot-Houllier
Grégory
G
Fulcrand
Géraldine
G
Jaulin
Christian
C
D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002842:Chromatids / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008677:Metaphase; D008938:Mitosis / Q000187:drug effects; D015739:Nocodazole / Q000494:pharmacology*; D010766:Phosphorylation; D008941:Spindle Apparatus / Q000187:drug effects*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D016203:CDC2 Protein Kinase; D006655:Histone Deacetylases; D015739:Nocodazole