Implications of enhancer of zeste homologue 2 expression in pancreatic ductal adenocarcinoma

Toll, Adam D.; Dasgupta, Abhijit; Potoczek, Magdalena; Yeo, Charles J.; Kleer, Celina G.; Brody, Jonathan R.; Witkiewicz, Agnieszka K.

doi:10.1016/j.humpath.2010.03.004

Cited by 60 publications

(67 citation statements)

References 16 publications

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“…Importantly, bioinformatic analysis of 2,158 human tumor specimens showed that the expression levels of EZH2 and KDM2B were closely correlated across tumor types (Supplemental Figure 7D) and in human PDAC specimens (Supplemental Figure 7E), and KDM2B showed the highest degree of coordinate regulation with EZH2 compared with all HDM family members (Supplemental Figure 7F). As silencing of PRC2 targets and induction of EZH2 are associated with poor differentiation and shortened survival across multiple cancer types, including PDAC (22,(27)(28)(29)(30), these data establish the widespread importance of cooperation between KDM2B and PcG proteins in antagonizing developmental decisions in cancer.…”

Section: Discussionmentioning

confidence: 75%

“…Consistent with direct roles of KDM2B in the regulation of these pathways, KDM2B overexpression in primary mouse Kras G12D -expressing pancreatic ductal cells induced a MYC transcriptional signature (Supplemental Figure 3A) and concomitantly repressed TP53 and PcG targets, as determined by RNA sequencing (RNA-seq) profiling (Supplemental Figure 3, A and B). The suggested functions of both MYC and PRC2 in the KDM2B transcriptome are notable in light of the known roles of these factors in driving progression of poorly differentiated cancers (26)(27)(28)(29)(30).…”

Section: Kdm2b Is Upregulated and Associated With Advanced Disease Inmentioning

confidence: 99%

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KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs

Tzatsos

Paskaleva²,

Ferrari³

et al. 2013

J. Clin. Invest.

125

160

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Epigenetic mechanisms mediate heritable control of cell identity in normal cells and cancer. We sought to identify epigenetic regulators driving the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal human cancers. We found that KDM2B (also known as Ndy1, FBXL10, and JHDM1B), an H3K36 histone demethylase implicated in bypass of cellular senescence and somatic cell reprogramming, is markedly overexpressed in human PDAC, with levels increasing with disease grade and stage, and highest expression in metastases. KDM2B silencing abrogated tumorigenicity of PDAC cell lines exhibiting loss of epithelial differentiation, whereas KDM2B overexpression cooperated with Kras G12D to promote PDAC formation in mouse models. Gain-and loss-of-function experiments coupled to genome-wide gene expression and ChIP studies revealed that KDM2B drives tumorigenicity through 2 different transcriptional mechanisms. KDM2B repressed developmental genes through cobinding with Polycomb group (PcG) proteins at transcriptional start sites, whereas it activated a module of metabolic genes, including mediators of protein synthesis and mitochondrial function, cobound by the MYC oncogene and the histone demethylase KDM5A. These results defined epigenetic programs through which KDM2B subverts cellular differentiation and drives the pathogenesis of an aggressive subset of PDAC.

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Section: Discussionmentioning

confidence: 75%

Section: Kdm2b Is Upregulated and Associated With Advanced Disease Inmentioning

confidence: 99%

KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs

Tzatsos

Paskaleva²,

Ferrari³

et al. 2013

J. Clin. Invest.

125

160

View full text Add to dashboard Cite

show abstract

“…EZH2 has a master regulatory role in the fate of native embryogenic cells (31), as well as in cancer development via methylation-mediated repression of the transcription of several genes (32,33). Overexpression of EZH2 is a marker of advanced and metastatic disease in many solid tumors, including cholangiocarcinoma (12,13,34). EZH2 is crucial for regulating the cell cycle by repressing several tumor-suppressor genes such as p16 INK4a , p27 KIP1 and RUNX3, and by mediating the pRb pathway.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells

et al. 2013

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Abstract. Enhancer of zeste homolog 2 (EZH2) is involved in malignant transformation and the biological aggressiveness of several human malignancies. Growing evidence indicates that EZH2 may be an appropriate therapeutic target for malignancies, including cholangiocarcinoma. Recently, an S-adenosyl-L-homocysteine hydrolase inhibitor, 3-deazaneplanocin A (DZNep) was shown to deplete and inhibit EZH2. The aim of this study was to determine the effect of DZNep and the combination of gemcitabine and DZNep in cholangiocarcinoma cells. The effects of DZNep and its combination with gemcitabine were assessed in the cholangiocarcinoma cell lines RBE and TFK-1. DZNep depleted the cellular levels of EZH2 and inhibited the associated histone H3 lysine 27 trimethylation. DZNep treatment resulted in the inhibition of proliferation in the cholangiocarcinoma cell lines, and the combination of DZNep and gemcitabine showed synergistic inhibition of cell proliferation. DZNep induced apoptosis and G1 phase cell cycle arrest in cholangiocarcinoma cells, and the combination of DZNep and gemcitabine enhanced the induced apoptosis and G1 arrest when compared with gemcitabine alone. Inhibition of cell proliferation by DZNep was partially associated with upregulation of p16INK4a and p17 KIP1. The present study shows that DZNep inhibits cell proliferation by inducing G1 arrest and apoptosis. These results indicate that an epigenetic therapy that pharmacologically targets EZH2 via DZNep may constitute a novel approach for the treatment of cholangiocarcinoma.

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“…For instance, in recent study by Mazur, et al, SMYD3, MLL5, EZH2, SETD5 and WHSC1L1 were found to be consistently upregulated in pancreatic cancer samples in a screen of 54 known and candidate human lysine methyltransferases, which are histone code writers [37]. Several studies had previously found EZH2 overexpression in pancreatic cancer [38–40]. Interestingly, the oncogenic mutant KRAS signal was found to increase the expression of EZH2 [41].…”

Section: Nucleosome Remodeling Machines and Histone Modifying Enzymesmentioning

confidence: 99%

The Triple-Code Model for Pancreatic Cancer

Lomberk¹,

Urrutia²

2015

Surgical Clinics of North America

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Pancreatic adenocarcinoma (PDAC) is a lethal and painful disease, which has become one of the most frequent causes of death by malignant diseases around the world. Unfortunately, for the most part, this disease remains incurable. Significant advances in the field of genetics, particularly during the last two decades, has led to the proposal of a progression model, by which this cancer evolves by the accumulation of mutations and deletions in key oncogenes and tumor suppressor genes. This model has been remarkably useful for the development of tumor markers as well as elegant animal models. In spite of these strengths, this model does not take into consideration concepts and methodologies that have been derived from the field of epigenetics nor studies in the field of nuclear structure and function. Since our laboratory has been long been an advocate of these changes as critical for the pathobiology of pancreatic cancer, in this article, we describe an updated, more comprehensive model, which includes these concepts. With the widespread utilization of next generation sequencing for identifying both genetic and epigenetic changes genome-wide, we believe that the framework of this model will help to further identify and validate not only more but better markers for pancreatic cancer. In addition, as opposed to genetic changes, epigenetic alterations are amenable to pharmacological manipulations, consequently the familiarization with this model will help to better understand the potential beneficial effects of this type of therapy for this disease. Thus, we are optimistic that this new integrated paradigm will contribute to advance this field of research not only from a mechanistic point of view, but also from a translational one.

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Implications of enhancer of zeste homologue 2 expression in pancreatic ductal adenocarcinoma

Cited by 60 publications

References 16 publications

KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs

KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs

Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells

The Triple-Code Model for Pancreatic Cancer

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