FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W365261944> ?p ?o ?g. }

• W365261944 abstract "Histone deacetylase inhibitors (HDACi) are a class of drug that has gained interest due to their selective cytotoxic properties. HDACi impose a range of effects in treated cells, including up and down regulation of transcription, cell cycle arrests, increased histone and non-histone protein lysine acetylation, aberrant mitotic phenotypes and apoptosis. In the treatment of cancer, traditional therapies are non-selective, typically targeting all actively cycling cells and thus targeting both healthy and cancerous tissue. HDACi have been identified to selectively impose checkpoint arrests in normal cells that confers a resistance to HDACi induced cell death, thus giving these agents an advantage over conventional chemotherapeutic agents, imposing a resistance conferring G2 arrest in primary cells, which is not functional in almost all tumour cells. These HDACi sensitive cells progress into mitosis, where chromosome alignment is disrupted coupled with the failure of the protective spindle assembly checkpoint. Cells undergo an aberrant mitotic division and apoptosis is induced in the subsequent G1. Due to their chemotherapeutic properties, HDACi have been trialled and approved for clinical use. However many actions of HDACi are still being elucidated. The nature of the G2 checkpoint arrest which confers resistance has not been identified. Cells which do not impose this protective checkpoint arrest enter mitosis. The application of HDACi during S phase causes cells to undergo an aberrant mitosis, where chromosomes fail to line up at the metaphase plate and the spindle assembly checkpoint is overridden. This thesis investigates the changes to histone H3 lysine 9 (Lys9) methylation induced by increased acetylation and whether this is involved in the mode of action of HDACi on sensitive cells. HDACi cause rapid increases to the level of histone acetylation, with this increase anticipated to have dramatic effects on other histone modifications, in particular the methylation of histone H3 lys9. Analysis of the acetylation and methylation patterns of histone H3 lys9 during the cell cycle after being treated with HDACi in S phase revealed that whilst increases to histone acetylation were rapid, reductions to the level of methylation on this site were minor and less dramatic than anticipated. The complete depletion of histone H3 lys9 trimethylation modifications by the overexpression of specific histone demethylases failed to induce aberrant mitosis in all mitotic cells identified. HDACi treated cells were progress through the G2/M phase of the cell cycle slower than untreated cells as determined by FACS analysis of individual cells. Creation of a cell line stably expressing a histone protein fused with the green fluorescent protein (H2B-GFP) allowed live cells to be visualised as they progressed through mitosis, and analysis of time lapse microscopy images allowed us to determine the cell cycle delay was specifically occurring in mitosis. Cell cycle variation of histone H3 lys9 methylation patterns in response to HDACi treatment was less affected than anticipated, based on the dramatically increased level of histone acetylation. The complete removal of trimethylation from this residue failed to induce aberrant mitosis. The mechanism of action of HDACi in inducing aberrant mitosis therefore seems to be independent of changes to histone H3 lys9 methylation and subsequent HP1 binding to this modified residue. Recent developments in this field have identified that changes to the level of other histone modifications on other sites may still be involved in the activation of the G2 checkpoint in resistant cells, the occurrence of an aberrant mitosis and the subsequent overriding of the spindle assembly checkpoint, all of which are hallmarks of HDACi treatment on cells." @default.
• W365261944 created "2016-06-24" @default.
• W365261944 creator A5013524698 @default.
• W365261944 date "2012-01-01" @default.
• W365261944 modified "2023-09-26" @default.
• W365261944 title "Investigating the mode of action of histone deacetylase inhibiting agents" @default.
• W365261944 hasPublicationYear "2012" @default.
• W365261944 type Work @default.
• W365261944 sameAs 365261944 @default.
• W365261944 citedByCount "0" @default.
• W365261944 crossrefType "journal-article" @default.
• W365261944 hasAuthorship W365261944A5013524698 @default.
• W365261944 hasConcept C104317684 @default.
• W365261944 hasConcept C105696609 @default.
• W365261944 hasConcept C119157956 @default.
• W365261944 hasConcept C1491633281 @default.
• W365261944 hasConcept C175732170 @default.
• W365261944 hasConcept C190283241 @default.
• W365261944 hasConcept C27253355 @default.
• W365261944 hasConcept C2776202225 @default.
• W365261944 hasConcept C2778305200 @default.
• W365261944 hasConcept C29537977 @default.
• W365261944 hasConcept C47432576 @default.
• W365261944 hasConcept C502942594 @default.
• W365261944 hasConcept C54086632 @default.
• W365261944 hasConcept C54355233 @default.
• W365261944 hasConcept C552990157 @default.
• W365261944 hasConcept C64927066 @default.
• W365261944 hasConcept C85813293 @default.
• W365261944 hasConcept C86803240 @default.
• W365261944 hasConcept C93304396 @default.
• W365261944 hasConcept C95444343 @default.
• W365261944 hasConceptScore W365261944C104317684 @default.
• W365261944 hasConceptScore W365261944C105696609 @default.
• W365261944 hasConceptScore W365261944C119157956 @default.
• W365261944 hasConceptScore W365261944C1491633281 @default.
• W365261944 hasConceptScore W365261944C175732170 @default.
• W365261944 hasConceptScore W365261944C190283241 @default.
• W365261944 hasConceptScore W365261944C27253355 @default.
• W365261944 hasConceptScore W365261944C2776202225 @default.
• W365261944 hasConceptScore W365261944C2778305200 @default.
• W365261944 hasConceptScore W365261944C29537977 @default.
• W365261944 hasConceptScore W365261944C47432576 @default.
• W365261944 hasConceptScore W365261944C502942594 @default.
• W365261944 hasConceptScore W365261944C54086632 @default.
• W365261944 hasConceptScore W365261944C54355233 @default.
• W365261944 hasConceptScore W365261944C552990157 @default.
• W365261944 hasConceptScore W365261944C64927066 @default.
• W365261944 hasConceptScore W365261944C85813293 @default.
• W365261944 hasConceptScore W365261944C86803240 @default.
• W365261944 hasConceptScore W365261944C93304396 @default.
• W365261944 hasConceptScore W365261944C95444343 @default.
• W365261944 hasLocation W3652619441 @default.
• W365261944 hasOpenAccess W365261944 @default.
• W365261944 hasPrimaryLocation W3652619441 @default.
• W365261944 hasRelatedWork W147184395 @default.
• W365261944 hasRelatedWork W1968031432 @default.
• W365261944 hasRelatedWork W2003130292 @default.
• W365261944 hasRelatedWork W2024281593 @default.
• W365261944 hasRelatedWork W2049847297 @default.
• W365261944 hasRelatedWork W2050331458 @default.
• W365261944 hasRelatedWork W2071699699 @default.
• W365261944 hasRelatedWork W2081973434 @default.
• W365261944 hasRelatedWork W2095154732 @default.
• W365261944 hasRelatedWork W2102371219 @default.
• W365261944 hasRelatedWork W2106768632 @default.
• W365261944 hasRelatedWork W2135994759 @default.
• W365261944 hasRelatedWork W2357266420 @default.
• W365261944 hasRelatedWork W2362290164 @default.
• W365261944 hasRelatedWork W2382782174 @default.
• W365261944 hasRelatedWork W2393541386 @default.
• W365261944 hasRelatedWork W2556403767 @default.
• W365261944 hasRelatedWork W2605137358 @default.
• W365261944 hasRelatedWork W2620172898 @default.
• W365261944 hasRelatedWork W3030972483 @default.
• W365261944 isParatext "false" @default.
• W365261944 isRetracted "false" @default.
• W365261944 magId "365261944" @default.
• W365261944 workType "article" @default.