Histone deacetylase inhibitors induce mitotic slippage

Stevens, Frankie; Beamish, Heather; Warrener, Robyn; Gabrielli, Brian

doi:10.1038/sj.onc.1210779

Cited by 80 publications

(107 citation statements)

References 38 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, in addition to their effects on gene transcription, HDAC inhibitors also induce effects on mitotic fidelity that are highly comparable with those we observe upon inhibition of CtBP expression or targeting of the CtBP chromatinmodifying complex. These effects include activation of the spindle assembly checkpoint, aberrant chromosomal segregation, failure of cytokinesis and reduced association of chromosomal passenger proteins with mitotic chromatin (Stevens et al, 2008;Eot-Houllier et al, 2009). At present, the mechanisms underlying these effects of HDACs are not known, and may be either through regulation of gene transcription or through direct modification of centromeric chromatin.…”

Section: Discussionmentioning

confidence: 99%

CtBPs promote mitotic fidelity through their activities in the cell nucleus

Birts

Bergman²,

Blaydes

2010

Oncogene

View full text Add to dashboard Cite

CtBPs form NADH-sensitive chromatin-modifying complexes, which link cellular metabolism to gene transcription. They also function in the cytoplasm to regulate Golgi fissioning; their inhibition can consequently cause a Golgidependent checkpoint in G 2 . We have recently identified a novel role of CtBPs in the maintenance of mitotic fidelity; inhibition of CtBP synthesis resulting in reduced association of aurora B with mitotic chromatin and aberrant segregation of chromosomes. Here, we demonstrate that it is the interaction of CtBPs with transcriptional regulators and/or chromatin-modifying enzymes in the cell nucleus, rather than their role in Golgi fission, which is critical for the maintenance of mitotic fidelity.

show abstract

Section: Discussionmentioning

confidence: 99%

CtBPs promote mitotic fidelity through their activities in the cell nucleus

Birts

Bergman²,

Blaydes

2010

Oncogene

View full text Add to dashboard Cite

show abstract

“…However, at similar submicromolar concentrations belinostat is unable to induce a strong mitotic arrest in the resistant DLBCL cell lines. Studies of the mitotic effects of HDACi in other cell types have established that, in addition to activating the SAC, they cause it to fail prematurely and induce apoptotic signaling 17,19,30,31 ). We therefore hypothesized that forced mitotic arrest in the resistant cells might sensitize them to belinostat-induced cytotoxicity.…”

Section: Resultsmentioning

confidence: 99%

“…15 In the current study we determined that cell lines sensitive to belinostat-induced cytotoxicity undergo mitotic arrest prior to initiation of apoptosis, consistent with reports showing that HDACi can activate the SAC. 17,19 HDAC inhibition causes destabilized interactions between microtubules (Mt) and kinetochores assembled at centromeres. 17,31 A recent study showed that aberrant acetylation of the Mt endbinding protein, EB1, prevents stable chromosome alignment at the metaphase plate.…”

Section: Discussionmentioning

confidence: 99%

“…17,19,31 In addition, HDACs appear to be necessary to maintain the SAC once it has been activated. 17,19,30,31 Based on these studies and our results we predict that vincristine induces prolonged activation of the SAC in the HDACi-resistant cell lines and belinostat causes it to fail. To address this hypothesis we examined the phosphorylation of BubR1, an event that indicates SAC activation.…”

Section: Belinostat Curtails Vincristine-induced Sac Activation and Cmentioning

confidence: 99%

“…However, continued exposure to HDACi can cause SAC failure, mitotic catastrophe or slippage, and the induction of pro-apoptotic signaling. [17][18][19] SAC activation is also a major mechanism attributed to the anti-tumor effectiveness of microtubule targeting therapies such as taxanes and vinca alkaloids. 20,21 These drugs are common in many first line therapeutic regimens including the R-CHOP combination used for most non-Hodgkin's lymphomas.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Rodrigues

Bhakta

et al. 2016

Cancer Biology & Therapy

View full text Add to dashboard Cite

Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent 5-year survival rate, highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in combination with a variety of other drugs. However, rational selection of companion therapeutics for HDACi is difficult due to their poorly-understood, celltype specific mechanisms of action. To address this, we developed a pre-clinical model system of sensitivity and resistance to the HDACi belinostat using DLBCL cell lines. In the current study, we demonstrate that cell lines sensitive to the cytotoxic effects of HDACi undergo early mitotic arrest prior to apoptosis. In contrast, HDACi-resistant cell lines complete mitosis after a short delay and arrest in G1. To force mitotic arrest in HDACi-resistant cell lines, we used low dose vincristine or paclitaxel in combination with belinostat and observed synergistic cytotoxicity. Belinostat curtails vincristine-induced mitotic arrest and triggers a strong apoptotic response associated with downregulated MCL-1 expression and upregulated BIM expression. Resistance to microtubule targeting agents (MTAs) has been associated with their propensity to induce polyploidy and thereby increase the probability of genomic instability that enables cancer progression. Co-treatment with belinostat effectively eliminated a vincristine-induced, actively cycling polyploid cell population. Our study demonstrates that vincristine sensitizes DLBCL cells to the cytotoxic effects of belinostat and that belinostat prevents polyploidy that could cause vincristine resistance. Our findings provide a rationale for using low dose MTAs in conjunction with HDACi as a potential therapeutic strategy for treatment of aggressive DLBCL.

show abstract

Analysis of HDACi-Induced Changes in Chromosomal Passenger Complex Localization

Unruhe-Knauf

Knauer

2016

Methods in Molecular Biology

View full text Add to dashboard Cite

The chromosomal passenger complex (CPC) is a key regulator of cell division. Its proper localization during the different phases of mitosis and cytokinesis is crucial for the exertion of its various functions. HDACi treatment has been demonstrated to disturb the centromeric localization of the CPC in tumor cells, thus leading to severe mitotic defects often followed by apoptosis. In this chapter, we describe how HDACi-induced changes of the CPC localization can be analyzed by indirect immunofluorescence using CPC-specific primary and fluorophore-coupled secondary antibodies followed by confocal microscopy.

show abstract

Histone deacetylase inhibitors induce mitotic slippage

Cited by 80 publications

References 38 publications

CtBPs promote mitotic fidelity through their activities in the cell nucleus

CtBPs promote mitotic fidelity through their activities in the cell nucleus

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

Analysis of HDACi-Induced Changes in Chromosomal Passenger Complex Localization

Contact Info

Product

Resources

About