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TP53-Status-Dependent Oncogenic EZH2 Activity in Pancreatic Cancer
SIMPLE SUMMARY: Epigenetic alterations contribute to the aggressiveness and therapy resistance of Pancreatic Ductal Adenocarcinoma (PDAC). However, epigenetic regulators, including Enhancer of Zeste Homolog 2 (EZH2), reveal a strong context-dependent activity. Our study aimed to examine the context-...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9320674/ https://www.ncbi.nlm.nih.gov/pubmed/35884510 http://dx.doi.org/10.3390/cancers14143451 |
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author | Versemann, Lennart Patil, Shilpa Steuber, Benjamin Zhang, Zhe Kopp, Waltraut Krawczyk, Hannah Elisa Kaulfuß, Silke Wollnik, Bernd Ströbel, Philipp Neesse, Albrecht Singh, Shiv K. Ellenrieder, Volker Hessmann, Elisabeth |
author_facet | Versemann, Lennart Patil, Shilpa Steuber, Benjamin Zhang, Zhe Kopp, Waltraut Krawczyk, Hannah Elisa Kaulfuß, Silke Wollnik, Bernd Ströbel, Philipp Neesse, Albrecht Singh, Shiv K. Ellenrieder, Volker Hessmann, Elisabeth |
author_sort | Versemann, Lennart |
collection | PubMed |
description | SIMPLE SUMMARY: Epigenetic alterations contribute to the aggressiveness and therapy resistance of Pancreatic Ductal Adenocarcinoma (PDAC). However, epigenetic regulators, including Enhancer of Zeste Homolog 2 (EZH2), reveal a strong context-dependent activity. Our study aimed to examine the context-defining molecular prerequisites of oncogenic EZH2 activity in PDAC to assess the therapeutic efficacy of targeting EZH2. Our preclinical study using diverse PDAC models demonstrates that the TP53 status determines oncogenic EZH2 activity. Only in TP53-wildtype (wt) PDAC subtypes was EZH2 blockade associated with a favorable PDAC prognosis mainly through cell-death response. We revealed that EZH2 depletion increases p53wt stability by the de-repression of CDKN2A. Therefore, our study provides preclinical evidence that an intact CDKN2A-p53wt axis is indispensable for a beneficial outcome of EZH2 depletion and highlights the significance of molecular stratification to improve epigenetic targeting in PDAC. ABSTRACT: Pancreatic Ductal Adenocarcinoma (PDAC) represents a lethal malignancy with a consistently poor outcome. Besides mutations in PDAC driver genes, the aggressive tumor biology of the disease and its remarkable therapy resistance are predominantly installed by potentially reversible epigenetic dysregulation. However, epigenetic regulators act in a context-dependent manner with opposing implication on tumor progression, thus critically determining the therapeutic efficacy of epigenetic targeting. Herein, we aimed at exploring the molecular prerequisites and underlying mechanisms of oncogenic Enhancer of Zeste Homolog 2 (EZH2) activity in PDAC progression. Preclinical studies in EZH2 proficient and deficient transgenic and orthotopic in vivo PDAC models and transcriptome analysis identified the TP53 status as a pivotal context-defining molecular cue determining oncogenic EZH2 activity in PDAC. Importantly, the induction of pro-apoptotic gene signatures and processes as well as a favorable PDAC prognosis upon EZH2 depletion were restricted to p53 wildtype (wt) PDAC subtypes. Mechanistically, we illustrate that EZH2 blockade de-represses CDKN2A transcription for the subsequent posttranslational stabilization of p53wt expression and function. Together, our findings suggest an intact CDKN2A-p53wt axis as a prerequisite for the anti-tumorigenic consequences of EZH2 depletion and emphasize the significance of molecular stratification for the successful implementation of epigenetic targeting in PDAC. |
format | Online Article Text |
id | pubmed-9320674 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-93206742022-07-27 TP53-Status-Dependent Oncogenic EZH2 Activity in Pancreatic Cancer Versemann, Lennart Patil, Shilpa Steuber, Benjamin Zhang, Zhe Kopp, Waltraut Krawczyk, Hannah Elisa Kaulfuß, Silke Wollnik, Bernd Ströbel, Philipp Neesse, Albrecht Singh, Shiv K. Ellenrieder, Volker Hessmann, Elisabeth Cancers (Basel) Article SIMPLE SUMMARY: Epigenetic alterations contribute to the aggressiveness and therapy resistance of Pancreatic Ductal Adenocarcinoma (PDAC). However, epigenetic regulators, including Enhancer of Zeste Homolog 2 (EZH2), reveal a strong context-dependent activity. Our study aimed to examine the context-defining molecular prerequisites of oncogenic EZH2 activity in PDAC to assess the therapeutic efficacy of targeting EZH2. Our preclinical study using diverse PDAC models demonstrates that the TP53 status determines oncogenic EZH2 activity. Only in TP53-wildtype (wt) PDAC subtypes was EZH2 blockade associated with a favorable PDAC prognosis mainly through cell-death response. We revealed that EZH2 depletion increases p53wt stability by the de-repression of CDKN2A. Therefore, our study provides preclinical evidence that an intact CDKN2A-p53wt axis is indispensable for a beneficial outcome of EZH2 depletion and highlights the significance of molecular stratification to improve epigenetic targeting in PDAC. ABSTRACT: Pancreatic Ductal Adenocarcinoma (PDAC) represents a lethal malignancy with a consistently poor outcome. Besides mutations in PDAC driver genes, the aggressive tumor biology of the disease and its remarkable therapy resistance are predominantly installed by potentially reversible epigenetic dysregulation. However, epigenetic regulators act in a context-dependent manner with opposing implication on tumor progression, thus critically determining the therapeutic efficacy of epigenetic targeting. Herein, we aimed at exploring the molecular prerequisites and underlying mechanisms of oncogenic Enhancer of Zeste Homolog 2 (EZH2) activity in PDAC progression. Preclinical studies in EZH2 proficient and deficient transgenic and orthotopic in vivo PDAC models and transcriptome analysis identified the TP53 status as a pivotal context-defining molecular cue determining oncogenic EZH2 activity in PDAC. Importantly, the induction of pro-apoptotic gene signatures and processes as well as a favorable PDAC prognosis upon EZH2 depletion were restricted to p53 wildtype (wt) PDAC subtypes. Mechanistically, we illustrate that EZH2 blockade de-represses CDKN2A transcription for the subsequent posttranslational stabilization of p53wt expression and function. Together, our findings suggest an intact CDKN2A-p53wt axis as a prerequisite for the anti-tumorigenic consequences of EZH2 depletion and emphasize the significance of molecular stratification for the successful implementation of epigenetic targeting in PDAC. MDPI 2022-07-15 /pmc/articles/PMC9320674/ /pubmed/35884510 http://dx.doi.org/10.3390/cancers14143451 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Versemann, Lennart Patil, Shilpa Steuber, Benjamin Zhang, Zhe Kopp, Waltraut Krawczyk, Hannah Elisa Kaulfuß, Silke Wollnik, Bernd Ströbel, Philipp Neesse, Albrecht Singh, Shiv K. Ellenrieder, Volker Hessmann, Elisabeth TP53-Status-Dependent Oncogenic EZH2 Activity in Pancreatic Cancer |
title | TP53-Status-Dependent Oncogenic EZH2 Activity in Pancreatic Cancer |
title_full | TP53-Status-Dependent Oncogenic EZH2 Activity in Pancreatic Cancer |
title_fullStr | TP53-Status-Dependent Oncogenic EZH2 Activity in Pancreatic Cancer |
title_full_unstemmed | TP53-Status-Dependent Oncogenic EZH2 Activity in Pancreatic Cancer |
title_short | TP53-Status-Dependent Oncogenic EZH2 Activity in Pancreatic Cancer |
title_sort | tp53-status-dependent oncogenic ezh2 activity in pancreatic cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9320674/ https://www.ncbi.nlm.nih.gov/pubmed/35884510 http://dx.doi.org/10.3390/cancers14143451 |
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