Context-Dependent Epigenetic Regulation of Nuclear Factor of Activated T Cells 1 in Pancreatic Plasticity

Chen, Nai‐Ming; Neeße, Albrecht; Dyck, M; Steuber, Benjamin; Köenig, Alexander; Lubeseder‐Martellato, Clara; Winter, Thore; Forster, Teresa; Bohnenberger, Hanibal; Kitz, Julia; Reuter‐Jessen, Kirsten; Griesmann, Heidi; Gaedcke, Jochen; Grade, Marian; Zhang, Jin‐San; Tsai, Wan–Chi; Siveke, Jens T.; Schildhaus, Hans–Ulrich; Ströbel, Philipp; Johnsen, Steven A.; Ellenrieder, Volker; Heßmann, Elisabeth

doi:10.1053/j.gastro.2017.01.043

Cited by 40 publications

(55 citation statements)

References 43 publications

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“…It has been found that imatinib could cause drug resistance via recruitment of EZH2 to the promoter region of the PTEN and then downregulates PTEN’s transcripts in leukemia patients [ 35 ]; moreover, cumulative evidences revealed that lncRNAs interacted with EZH2 and recruited it to genes’ promoter regions to repress genes’ expression [ 36 – 38 ]. Furthermore, Chen NM and colleagues found that KRAS signaling was required for EZH2-mediated transcriptional activation of the inflammatory transcription factor nuclear factor of activated T cells 1 (NFATC1) in pancreatic ductal adenocarcinoma cells [ 39 ]. All these suggest that drugs, lncRNA, and transcription factor, may contribute to the binding of EZH2 to PTEN promoter.…”

Section: Discussionmentioning

confidence: 99%

The polycomb group protein EZH2 induces epithelial–mesenchymal transition and pluripotent phenotype of gastric cancer cells by binding to PTEN promoter

et al. 2018

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BackgroundThe influences of oncogenic Ezh2 on the progression and prognosis of gastric cancer (GC) and the underlying mechanisms are still poorly understood. Here, we aimed at investigating clinicopathological significance of Ezh2 in GC and the mechanisms underlying its function in GC development.MethodsThe expression level of Ezh2 was determined by qRT-PCR, immunoblot, and immunohistochemistry analysis in 156 pairs of GC tissues and adjacent normal gastric mucosa tissues. The biological functions of Ezh2 were assessed by in vitro and in vivo functional experiments. Chromatin immunoprecipitation (ChIP), luciferase, and Western blotting analyses were utilized to identify the relationship between Ezh2 and the PTEN/Akt signaling.ResultsThe expression of Ezh2 was higher in gastric cancer tissues in comparison with para-nontumorous epithelium. High expression of Ezh2 was associated with more aggressive biological behavior and poor prognosis in GC. In vitro studies indicated that Ezh2 promoted GC cells’ proliferation and clonogenicity. Besides, Ezh2 led to the acquisition of epithelial–mesenchymal transition (EMT) phenotype of GC cells and enhanced GC cell migration and invasion capacity. In particular, Ezh2 strengthened sphere-forming capacity of GC cells, indicating its role in the enrichment of GC stem cells. Furthermore, we found that PTEN/Akt signaling contributed to the effects of Ezh2 on cancer stem cells (CSC) and EMT phenotype in GC cells, and blocking PTEN signaling significantly rescued the effects of Ezh2.ConclusionsTaken together, Ezh2 has a central role in regulating diverse aspects of the pathogenesis of GC in part by involving PTEN/Akt signaling, indicating that it could be an independent prognostic factor and potential therapeutic target.Electronic supplementary materialThe online version of this article (10.1186/s13045-017-0547-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The polycomb group protein EZH2 induces epithelial–mesenchymal transition and pluripotent phenotype of gastric cancer cells by binding to PTEN promoter

et al. 2018

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“…Some epigenetic drugs have been already tested in PDA with promising results, 62 but no effects on immune infiltrating cells have been described. In particular, inhibition of histone methyltransferases, by Enhancer Of Zeste Homolog (EZH) 2 or histone deacetylases (HDACs), significantly impaired PDA progression, with EZH2 interfering with the oncogenic activity of NFATC1 and HDACs promoting epithelial gene expression, [63][64][65][66] but there is no mention about their effect on TILs.…”

Section: Discussionmentioning

confidence: 99%

Depletion of tumor-associated macrophages switches the epigenetic profile of pancreatic cancer infiltrating T cells and restores their anti-tumor phenotype

et al. 2017

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Pancreatic Ductal Adenocarcinoma (PDA) is characterized by a complex tumor microenvironment that supports its progression, aggressiveness and resistance to therapies. The delicate interplay between cancer and immune cells creates the conditions for PDA development, particularly due to the functional suppression of T cell anti-tumor effector activity. However, some of the mechanisms involved in this process are still poorly understood. In this study, we analyze whether the functional and epigenetic profile of T cells that infiltrate PDA is modulated by the microenvironment, and in particular by tumor-associated macrophages (TAMs). CD4 and CD8 T cells obtained from mice orthotopically injected with syngeneic PDA cells, and untreated or treated with Trabectedin, a cytotoxic drug that specifically targets TAMs, were sorted and analyzed by flow cytometry and characterized for their epigenetic profile. Assessment of cytokine production and the epigenetic profile of genes coding for IL10, T-bet and PD1 revealed that T cells that infiltrated PDA displayed activated promoter and repressed activity, in agreement with their regulatory phenotype (IL10/IFNγ, PD1). By contrast, in Trabectedin-treated mice, PDA-infiltrating T cells displayed repressed and and activated promoter activity, in accordance with their anti-tumor effector phenotype (IL10/IFNγ), indicating a key role of TAMs in orchestrating functions of PDA-infiltrating T cells by modulating their epigenetic profile towards a pro-tumoral phenotype. These results suggest the targeting of TAMs as an efficient strategy to obtain an appropriate T cell anti-tumor immune response and open new potential combinations for PDA treatment.

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“…These positive regulatory effects of EZH2 on NFATc1 were not observed in the PRC2 target gene Hoxa10, suggesting that oncogenic activation of Kras selectively alters the activity of EZH2 on a subset of target genes. These results highlight the plasticity of histone-modifying enzymes in the regulation of regeneration and tumorigenesis [49].…”

Section: Histone Methylation In Pancreatic Carcinogenesismentioning

confidence: 71%

“…An early study in PDAC defined an important role for EZH2 in silencing the tumor suppressor CDKN1B (p27) in poorly differentiated PDACs [48]. More recently, Chen and colleagues described the context-specific roles of EZH2 in the regulation of NFATc1 expression during pancreatic regeneration and tumorigenesis [49]. Employing pancreatitis models in mice, the authors found that NFATc1 was activated in acinar cells after injury and was silenced by EZH2-mediated H2K27me3 at its promoter during the late stages of regeneration.…”

Section: Histone Methylation In Pancreatic Carcinogenesismentioning

confidence: 99%

Recent Advances in Chromatin Mechanisms Controlling Pancreatic Carcinogenesis

Hank

Liss

2018

Epigenomes

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Pancreatic ductal adenocarcinoma has a heterogeneous genetic landscape, marked by frequent mutation of KRAS, CDKN2A, TP53, and SMAD4, resulting in poor responses to conventional therapeutic regimens. Over the past decade, increased understanding of the genetic underpinnings of this lethal cancer has yielded several different characterizations of pancreatic cancer subtypes. However, not all phenotypes and changes in pancreatic cancer can be explained by these findings. New insights on epigenetic modifications associated with pancreatic carcinogenesis have highlighted additional pathways, other than gene mutations, among which chromatin regulation plays a dominant role. Gene expression is highly regulated by subtle changes in chromatin configuration. The underlying mechanism is dominated by reversible post-translational histone modifications. In addition, there is growing evidence that different chromatin mechanisms interact with one another, contributing to the diversity of pancreatic carcinogenesis. This review highlights recent work characterizing chromatin regulatory mechanisms associated with pancreatic carcinogenesis as well as future directions of this emerging research.

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Context-Dependent Epigenetic Regulation of Nuclear Factor of Activated T Cells 1 in Pancreatic Plasticity

Cited by 40 publications

References 43 publications

The polycomb group protein EZH2 induces epithelial–mesenchymal transition and pluripotent phenotype of gastric cancer cells by binding to PTEN promoter

The polycomb group protein EZH2 induces epithelial–mesenchymal transition and pluripotent phenotype of gastric cancer cells by binding to PTEN promoter

Depletion of tumor-associated macrophages switches the epigenetic profile of pancreatic cancer infiltrating T cells and restores their anti-tumor phenotype

Recent Advances in Chromatin Mechanisms Controlling Pancreatic Carcinogenesis

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