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  2. Johannes Gutenberg-Universität Mainz
  3. DFG-491381577-H
Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-8352
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dc.contributor.authorKiweler, Nicole-
dc.contributor.authorSchwarz, Helena-
dc.contributor.authorNguyen, Alexandra-
dc.contributor.authorMatschos, Stephanie-
dc.contributor.authorMullins, Christina-
dc.contributor.authorPiée-Staffa, Andrea-
dc.contributor.authorBrachetti, Christina-
dc.contributor.authorRoos, Wynand P.-
dc.contributor.authorSchneider, Günter-
dc.contributor.authorLinnebacher, Michael-
dc.contributor.authorBrenner, Walburgis-
dc.contributor.authorKrämer, Oliver H.-
dc.date.accessioned2023-01-30T09:22:39Z-
dc.date.available2023-01-30T09:22:39Z-
dc.date.issued2022-
dc.identifier.urihttps://openscience.ub.uni-mainz.de/handle/20.500.12030/8368-
dc.description.abstractThe epigenetic modifier histone deacetylase-2 (HDAC2) is frequently dysregulated in colon cancer cells. Microsatellite instability (MSI), an unfaithful replication of DNA at nucleotide repeats, occurs in about 15% of human colon tumors. MSI promotes a genetic frameshift and consequently a loss of HDAC2 in up to 43% of these tumors. We show that long-term and short-term cultures of colorectal cancers with MSI contain subpopulations of cells lacking HDAC2. These can be isolated as single cell-derived, proliferating populations. Xenografted patient-derived colon cancer tissues with MSI also show variable patterns of HDAC2 expression in mice. HDAC2-positive and HDAC2-negative RKO cells respond similarly to pharmacological inhibitors of the class I HDACs HDAC1/HDAC2/HDAC3. In contrast to this similarity, HDAC2-negative and HDAC2-positive RKO cells undergo differential cell cycle arrest and apoptosis induction in response to the frequently used chemotherapeutic 5-fluorouracil, which becomes incorporated into and damages RNA and DNA. 5-fluorouracil causes an enrichment of HDAC2-negative RKO cells in vitro and in a subset of primary colorectal tumors in mice. 5-fluorouracil induces the phosphorylation of KAP1, a target of the checkpoint kinase ataxia-telangiectasia mutated (ATM), stronger in HDAC2-negative cells than in their HDAC2-positive counterparts. Pharmacological inhibition of ATM sensitizes RKO cells to cytotoxic effects of 5-fluorouracil. These findings demonstrate that HDAC2 and ATM modulate the responses of colorectal cancer cells towards 5-FU.en_GB
dc.description.sponsorshipGefördert durch die Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 491381577de
dc.language.isoengde
dc.rightsCC BY*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subject.ddc610 Medizinde_DE
dc.subject.ddc610 Medical sciencesen_GB
dc.titleThe epigenetic modifier HDAC2 and the checkpoint kinase ATM determine the responses of microsatellite instable colorectal cancer cells to 5-fluorouracilen_GB
dc.typeZeitschriftenaufsatzde
dc.identifier.doihttp://doi.org/10.25358/openscience-8352-
jgu.type.dinitypearticleen_GB
jgu.type.versionPublished versionde
jgu.type.resourceTextde
jgu.organisation.departmentFB 04 Medizinde
jgu.organisation.number2700-
jgu.organisation.nameJohannes Gutenberg-Universität Mainz-
jgu.rights.accessrightsopenAccess-
jgu.journal.titleCell biology and toxicologyde
jgu.journal.volumeVersion of Record (VoR)de
jgu.publisher.year2022-
jgu.publisher.nameSpringer Science + Business Media B.V.de
jgu.publisher.placeDordrechtde
jgu.publisher.issn1573-6822de
jgu.organisation.placeMainz-
jgu.subject.ddccode610de
jgu.publisher.doi10.1007/s10565-022-09731-3de
jgu.organisation.rorhttps://ror.org/023b0x485-
jgu.subject.dfgLebenswissenschaftende
Appears in collections:DFG-491381577-H

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