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dc.contributor.authorLedaki, Ien
dc.contributor.authorMcIntyre, Aen
dc.contributor.authorWigfield, Sen
dc.contributor.authorBuffa, Fen
dc.contributor.authorMcGowan, Sen
dc.contributor.authorBaban, Den
dc.contributor.authorLi, J-Len
dc.contributor.authorHarris, ALen
dc.date.accessioned2016-08-09T14:47:08Z
dc.date.available2016-08-09T14:47:08Z
dc.date.issued2015-08-14en
dc.identifier.urihttp://hdl.handle.net/10026.1/5245
dc.description.abstract

Carbonic anhydrase IX (CAIX) is strongly induced by hypoxia and its overexpression is associated with poor therapeutic outcome in cancer. Here, we report that hypoxia promotes tumour heterogeneity through the epigenetic regulation of CAIX. Based on hypoxic CAIX expression we identify and characterize two distinct populations of tumour cells, one that has inducible expression of CAIX and one that does not. The CAIX+ve population is enriched with cells expressing cancer stem cell markers and which have high self-renewal capacity. We show that differential CAIX expression is due to differences in chromatin structure. To further investigate the relationship between chromatin organization and hypoxic induction of CAIX expression we investigated the effect of JQ1 an inhibitor of BET bromodomain proteins and A366 a selective inhibitor of the H3K9 methyltransferase G9a/GLP. We identified that these drugs were able to modulate hypoxic CAIX expression induction. This further highlights the role of epigenetic modification in adaption to hypoxia and also in regulation of heterogeneity of cells within tumours. Interestingly, we identified that the two subpopulations show a differential sensitivity to HDAC inhibitors, NaBu or SAHA, with the CAIX positive showing greater sensitivity to treatment. We propose that drugs modulating chromatin regulation of expression may be used to reduce heterogeneity induced by hypoxia and could in combination have significant clinical consequences.

en
dc.format.extent19413 - 19427en
dc.languageengen
dc.language.isoengen
dc.subjectEMTen
dc.subjectcarbonic anhydrase IXen
dc.subjecthypoxiaen
dc.subjectstem cellsen
dc.subjecttumour heterogeneityen
dc.subjectAnimalsen
dc.subjectAntigens, Neoplasmen
dc.subjectCarbonic Anhydrase IXen
dc.subjectCarbonic Anhydrasesen
dc.subjectCell Hypoxiaen
dc.subjectCell Line, Tumoren
dc.subjectEnzyme Inductionen
dc.subjectFemaleen
dc.subjectHCT116 Cellsen
dc.subjectHeterograftsen
dc.subjectHistone Deacetylase Inhibitorsen
dc.subjectHumansen
dc.subjectIsoenzymesen
dc.subjectMCF-7 Cellsen
dc.subjectMaleen
dc.subjectMiceen
dc.subjectMice, Inbred BALB Cen
dc.subjectMice, Nudeen
dc.subjectNeoplastic Stem Cellsen
dc.titleCarbonic anhydrase IX induction defines a heterogeneous cancer cell response to hypoxia and mediates stem cell-like properties and sensitivity to HDAC inhibition.en
dc.typeJournal Article
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/26305601en
plymouth.issue23en
plymouth.volume6en
plymouth.publication-statusPublisheden
plymouth.journalOncotargeten
dc.identifier.doi10.18632/oncotarget.4989en
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine/UoA01 Clinical Medicine
dc.publisher.placeUnited Statesen
dcterms.dateAccepted2015-07-16en
dc.identifier.eissn1949-2553en
dc.rights.embargoperiodNot knownen
rioxxterms.versionofrecord10.18632/oncotarget.4989en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-08-14en
rioxxterms.typeJournal Article/Reviewen


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