Histone deacetylase inhibitors induce premature sister chromatid separation and override the mitotic spindle assembly checkpoint - PubMed (original) (raw)
Histone deacetylase inhibitors induce premature sister chromatid separation and override the mitotic spindle assembly checkpoint
Laura Magnaghi-Jaulin et al. Cancer Res. 2007.
Abstract
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.
Similar articles
- Histone deacetylase inhibitors induce mitotic slippage.
Stevens FE, Beamish H, Warrener R, Gabrielli B. Stevens FE, et al. Oncogene. 2008 Feb 28;27(10):1345-54. doi: 10.1038/sj.onc.1210779. Epub 2007 Sep 10. Oncogene. 2008. PMID: 17828304 - Inhibition of histone deacetylase activity increases chromosomal instability by the aberrant regulation of mitotic checkpoint activation.
Shin HJ, Baek KH, Jeon AH, Kim SJ, Jang KL, Sung YC, Kim CM, Lee CW. Shin HJ, et al. Oncogene. 2003 Jun 19;22(25):3853-8. doi: 10.1038/sj.onc.1206502. Oncogene. 2003. PMID: 12813458 - Analysis of checkpoint responses to histone deacetylase inhibitors.
Beamish H, Warrener R, Gabrielli BG. Beamish H, et al. Methods Mol Biol. 2004;281:245-59. doi: 10.1385/1-59259-811-0:245. Methods Mol Biol. 2004. PMID: 15220534 - Histone deacetylase inhibitors: molecular mechanisms of action.
Xu WS, Parmigiani RB, Marks PA. Xu WS, et al. Oncogene. 2007 Aug 13;26(37):5541-52. doi: 10.1038/sj.onc.1210620. Oncogene. 2007. PMID: 17694093 Review. - Prospects: histone deacetylase inhibitors.
Dokmanovic M, Marks PA. Dokmanovic M, et al. J Cell Biochem. 2005 Oct 1;96(2):293-304. doi: 10.1002/jcb.20532. J Cell Biochem. 2005. PMID: 16088937 Review.
Cited by
- A new class of cytotoxic agents targets tubulin and disrupts microtubule dynamics.
Al-Hamashi AA, Koranne R, Dlamini S, Alqahtani A, Karaj E, Rashid MS, Knoff JR, Dunworth M, Pflum MKH, Casero RA Jr, Perera L, Taylor WR, Tillekeratne LMV. Al-Hamashi AA, et al. Bioorg Chem. 2021 Nov;116:105297. doi: 10.1016/j.bioorg.2021.105297. Epub 2021 Aug 30. Bioorg Chem. 2021. PMID: 34509798 Free PMC article. - DNA-PKcs inhibition impairs HDAC6-mediated HSP90 chaperone function on Aurora A and enhances HDACs inhibitor-induced cell killing by increasing mitotic aberrant spindle assembly.
Yu L, Lang Y, Guo J, Cai J, Shang ZF, Chen BPC. Yu L, et al. Cell Cycle. 2021 Jan;20(2):211-224. doi: 10.1080/15384101.2020.1867790. Epub 2021 Jan 6. Cell Cycle. 2021. PMID: 33404279 Free PMC article. - S-phase transcriptional buffering quantified on two different promoters.
Yunger S, Kafri P, Rosenfeld L, Greenberg E, Kinor N, Garini Y, Shav-Tal Y. Yunger S, et al. Life Sci Alliance. 2018 Sep 19;1(5):e201800086. doi: 10.26508/lsa.201800086. eCollection 2018 Oct. Life Sci Alliance. 2018. PMID: 30456379 Free PMC article. - Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models.
Huang P, Almeciga-Pinto I, Jarpe M, van Duzer JH, Mazitschek R, Yang M, Jones SS, Quayle SN. Huang P, et al. Oncotarget. 2017 Jan 10;8(2):2694-2707. doi: 10.18632/oncotarget.13738. Oncotarget. 2017. PMID: 27926524 Free PMC article. - Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma.
Havas AP, Rodrigues KB, Bhakta A, Demirjian JA, Hahn S, Tran J, Scavello M, Tula-Sanchez AA, Zeng Y, Schmelz M, Smith CL. Havas AP, et al. Cancer Biol Ther. 2016 Dec;17(12):1240-1252. doi: 10.1080/15384047.2016.1250046. Epub 2016 Oct 28. Cancer Biol Ther. 2016. PMID: 27791595 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources