| dc.contributor.advisor | Hessmann, Elisabeth Prof. Dr. | |
| dc.contributor.author | Versemann, Lennart Viktor | |
| dc.date.accessioned | 2022-07-14T10:57:17Z | |
| dc.date.available | 2023-06-30T00:50:10Z | |
| dc.date.issued | 2022-07-14 | |
| dc.identifier.uri | http://resolver.sub.uni-goettingen.de/purl?ediss-11858/14153 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-9359 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
| dc.subject.ddc | 610 | |
| dc.title | TP53-status dependent oncogenic EZH2 Activity in Pancreatic Cancer | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Hessmann, Elisabeth Prof. Dr. | |
| dc.date.examination | 2022-06-14 | de |
| dc.description.abstracteng | Pancreatic Ductal Adenocarcinoma (PDAC) remains a dismal malignancy with a 5-year sur-vival rate of less than 10%. Predominately, chemoresistance mediated by the dynamic cel-lular plasticity induced through epigenetic alterations accounts for the high mortality rates of PDAC. The histone methyltransferase enhancer of zeste homolog 2 (EZH2), the catalytic component of the polycomb repressive complex 2 (PRC2), is frequently found overex-pressed in PDAC and has crucial functions in the evasion of tumor-suppressive mecha-nisms. However, recent studies suggest a huge context-dependency of oncogenic EZH2 activity.
The tumor suppressor p53 is well characterized for its anti-tumorigenic capacities. However, in human PDAC, TP53 mutations occur with a prevalence of 50-80%, potentially resulting in the loss of tumor suppressor function and the gain of oncogenic function suggesting a TP53-status-dependent functional behaviour of a cell. However, whether and to what extent mutations of TP53 indeed functionally or mechanistically influence EZH2-dependent pro-cesses in PDAC remains largely elusive. In this study, the impact of a specific genetic back-ground on the activity of epigenetic processes has been investigated. The major aim was to illuminate TP53-status-dependent oncogenic EZH2 activity in PDAC progression.
Functionally, we demonstrate that EZH2-dependent target gene regulation is determined by the TP53-status and that EZH2 depletion correlates with a better prognosis only in TP53wt PDAC. Moreover, we reveal that EZH2 depletion combined with chemotherapy in-creases apoptosis induction restrictively in TP53wt cells. Hence, our study highlights a strong context-dependency of the EZH2 activity specifically regarding the TP53-status. Therefore, our data suggest that in PDAC subtypes with TP53wt-status, EZH2 depletion together with chemotherapy might represent a beneficial strategy to tackle PDAC, whereas in TP53-mutant PDAC, EZH2 depletion is not advantageous.
Furthermore, our findings imply that EZH2 influences p53wt expression on a post-transla-tional level and illustrate that EZH2 targets the CDKN2A gene for transcriptional repression, thus abrogating p14ARF/p19Arf-dependent inhibition of Mdm2-mediated p53 degradation. Moreover, we reveal that PDAC formation is promoted despite TP53wt-status and low EZH2 expression, if EZH2-independent CDKN2A repression occurs, thus demonstrating the im-portance of an intact CDKN2A-TP53wt axis for a beneficial outcome of EZH2 inhibition in PDAC. Moreover, we revealed the existence of a previously unknown EZH2-p53-complex in PDAC, suggesting that also non-canonical functions of EZH2 may contribute to PDAC progression.
Conclusively, our data underline the significance of patient stratification to predict and im-prove EZH2 inhibition as a potential treatment strategy in PDAC. | de |
| dc.contributor.coReferee | Dobbelstein, Matthias Prof. Dr. | |
| dc.subject.eng | Pancreatic Cancer | de |
| dc.subject.eng | Epigenetics | de |
| dc.subject.eng | EZH2 | de |
| dc.subject.eng | p53 | de |
| dc.subject.eng | CDKN2A | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-ediss-14153-7 | |
| dc.affiliation.institute | Medizinische Fakultät | |
| dc.subject.gokfull | Innere Medizin - Allgemein- und Gesamtdarstellungen (PPN619875747) | de |
| dc.subject.gokfull | Gastroenterologie (PPN61987578X) | de |
| dc.subject.gokfull | Onkologie (PPN619875895) | de |
| dc.description.embargoed | 2023-06-30 | de |
| dc.identifier.ppn | 1810676584 | |
| dc.identifier.orcid | 0000-0003-2104-8700 | de |
| dc.notes.confirmationsent | Confirmation sent 2022-07-14T11:15:01 | de |