EZH2-GATA6 axis in Pancreatic ductal adenocarcinoma

by Shilpa Patil
Doctoral thesis
Date of Examination:2020-06-22
Date of issue:2020-09-25
Advisor:Dr. Elisabeth Pd Heßmann
Referee:PD Dr. Elisabeth Heßmann
Referee:Prof. Dr. Matthias Dobbelstein
Referee:Prof. Dr. Frauke Alves
Referee:Prof. Dr. Dieter Kube
Referee:Prof. Dr. Heidi Hahn
Referee:PD Dr. Laura C. Zelarayán
Persistent Address: http://dx.doi.org/10.53846/goediss-8223

 

 

Files in this item

Name:Ph.D. Thesis_Shilpa.pdf
Size:4.57Mb
Format:PDF

The following license files are associated with this item:

Abstract

English

Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous disease which is significantly driven by epigenetic alterations, e.g. installed by overexpression of Enhancer of Zeste homologue 2 (EZH2). EZH2 constitutes the catalytic member of the PRC2 complex and plays a pivotal role in gene repression by mediating histone methylation (H3K27me3). High EZH2 expression levels are predominantly found in undifferentiated PDAC tumors and are associated with poor prognosis. However, the underlying mechanisms that bridge EZH2 activity to PDAC dedifferentiation remain elusive. Here we aim to dissect the mechanistic and functional role of EZH2 in PDAC progression and dedifferentiation. The functional implications of EZH2 are investigated in vitro in primary PDAC cells upon genetic (CRISPR/Cas9 and shRNA-based) or pharmacological inhibition (EPZ6438) of EZH2 and in vivo utilizing transgenic mice of EZH2 deficiency and Patient-Derived-Xenograft (PDX) models. EZH2-dependent gene signatures are identified based on ChIP-and RNA-seq analyses and are further validated by independent gene expression studies. EZH2 activity correlates with increased tumor incidence and metastatic propensity in murine PDAC and drives dedifferentiation in human PDAC. Blockade of the histone methyltransferase reduces proliferation, invasion and stemness features in PDAC cells. Accordingly, genome wide binding- and expression analyses reveal EZH2 as a repressor of differentiation-associated gene signatures and indicate that blockage of EZH2 activity induces a gene signature shift towards classical and less aggressive molecular PDAC subtypes. The endodermal transcription factor encoding GATA6 gene is identified as one of the most significantly regulated direct EZH2 targets. Consequently, abrogation of GATA6 upregulation in the context of EZH2-deficiency partially counteracts the acquisition of classical gene signatures and reinstalls their invasive capacities of PDAC cells, suggesting that the tumorigenic activity of EZH2 is critically determined by GATA6 repression. Together, our findings link the EZH2-GATA6 axis to PDAC subtype identity and suggest EZH2 inhibition as a promising therapeutic strategy to induce subtype-switching in favor of a less aggressive PDAC phenotype.
Keywords: EZH2; GATA6; PDAC subtype; Pancreatic cancer; Epigenetics
 
Statistik