TP53-status dependent oncogenic EZH2 Activity in Pancreatic Cancer

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.2023-06-3