Bitte benutzen Sie diese Kennung, um auf die Ressource zu verweisen:
http://doi.org/10.25358/openscience-8352
Autoren: | Kiweler, Nicole Schwarz, Helena Nguyen, Alexandra Matschos, Stephanie Mullins, Christina Piée-Staffa, Andrea Brachetti, Christina Roos, Wynand P. Schneider, Günter Linnebacher, Michael Brenner, Walburgis Krämer, Oliver H. |
Titel: | The epigenetic modifier HDAC2 and the checkpoint kinase ATM determine the responses of microsatellite instable colorectal cancer cells to 5-fluorouracil |
Online-Publikationsdatum: | 30-Jan-2023 |
Erscheinungsdatum: | 2022 |
Sprache des Dokuments: | Englisch |
Zusammenfassung/Abstract: | The 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. |
DDC-Sachgruppe: | 610 Medizin 610 Medical sciences |
Veröffentlichende Institution: | Johannes Gutenberg-Universität Mainz |
Organisationseinheit: | FB 04 Medizin |
Veröffentlichungsort: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-8352 |
Version: | Published version |
Publikationstyp: | Zeitschriftenaufsatz |
Nutzungsrechte: | CC BY |
Informationen zu den Nutzungsrechten: | https://creativecommons.org/licenses/by/4.0/ |
Zeitschrift: | Cell biology and toxicology Version of Record (VoR) |
Verlag: | Springer Science + Business Media B.V. |
Verlagsort: | Dordrecht |
Erscheinungsdatum: | 2022 |
ISSN: | 1573-6822 |
DOI der Originalveröffentlichung: | 10.1007/s10565-022-09731-3 |
Enthalten in den Sammlungen: | DFG-491381577-H |
Dateien zu dieser Ressource:
Datei | Beschreibung | Größe | Format | ||
---|---|---|---|---|---|
the_epigenetic_modifier_hdac2-20221121091002948.pdf | 1.97 MB | Adobe PDF | Öffnen/Anzeigen |