Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb-repressive complex 2 (PRC2) that represses gene transcription through histone H3 lysine 27 trimethylation (H3K27me3). Although EZH2 is abundantly present in various cancers, the molecular consequences leading to oncogenesis remain unclear. Here, we show that EZH2 concordantly silences the Wnt pathway antagonists operating at several subcellular compartments, which in turn activate Wnt/β-catenin signaling in hepatocellular carcinomas (HCC). Chromatin immunoprecipitation promoter array and gene expression analyses in HCCs revealed EZH2 occupancy and reduced expression of Wnt antagonists, including the growth-suppressive AXIN2, NKD1, PPP2R2B, PRICKLE1, and SFRP5. Knockdown of EZH2 reduced the promoter occupancy of PRC2, histone deacetylase 1 (HDAC1), and H3K27me3, whereas the activating histone marks were increased, leading to the transcriptional upregulation of the Wnt antagonists. Combinatorial EZH2 and HDAC inhibition dramatically reduced the levels of nuclear β-catenin, T-cell factor-dependent transcriptional activity, and downstream pro-proliferative targets CCND1 and EGFR. Functional analysis revealed that downregulation of EZH2 reduced HCC cell growth, partially through the inhibition of β-catenin signaling. Conversely, ectopic overexpression of EZH2 in immortalized hepatocytes activated Wnt/β-catenin signaling to promote cellular proliferation. In human HCCs, concomitant overexpression of EZH2 and β-catenin was observed in one-third (61/179) of cases and significantly correlated with tumor progression. Our data indicate that EZH2-mediated epigenetic silencing contributes to constitutive activation of Wnt/β-catenin signaling and consequential proliferation of HCC cells, thus representing a novel therapeutic target for this highly malignant tumor.
"In detail, we identified the up-regulation of the pro-apoptotic caspase 8 (CASP8) , the tumor suppressors P67/methionyl aminopeptidase 2 (P67/MetAP2) , pyruvate dehydrogenase [lipoamide] kinase isozyme 4 (PDK4)  and protein angiopoietin-like 4 (ANGPTL4)  (which is suppressed in HCC when compared to perilesional tissue ), and of different genes known to be suppressed in HCC (i.e. CD82 ; WNT antagonist prickle homolog 1, PRICKLE1 ) and other neoplasms (i.e. DAZ associated protein 2, DAZAP2 ). "
[Show abstract][Hide abstract] ABSTRACT: Background & Aims
Liver regeneration (LR) is a valuable model for studying mechanisms modulating hepatocyte proliferation. Nuclear receptors (NRs) are key players in the control of cellular functions, being ideal modulators of hepatic proliferation and carcinogenesis.
Methods & Results
We used a previously validated RT-qPCR platform to profile modifications in the expression of all 49 members of the NR superfamily in mouse liver during LR. Twenty-nine NR transcripts were significantly modified in their expression during LR, including fatty acid (peroxisome proliferator-activated receptors, PPARs) and oxysterol (liver X receptors, Lxrs) sensors, circadian masters RevErbα and RevErbβ, glucocorticoid receptor (Gr) and constitutive androxane receptor (Car). In order to detect the NRs that better characterize proliferative status vs. proliferating liver, we used the novel Random Forest (RF) analysis to selected a trio of down-regulated NRs (thyroid receptor alpha, Trα; farsenoid X receptor beta, Fxrβ; Pparδ) as best discriminators of the proliferating status. To validate our approach, we further studied PPARδ role in modulating hepatic proliferation. We first confirmed the suppression of PPARδ both in LR and human hepatocellular carcinoma at protein level, and then demonstrated that PPARδ agonist GW501516 reduces the proliferative potential of hepatoma cells.
Our data suggest that NR transcriptome is modulated in proliferating liver and is a source of biomarkers and bona fide pharmacological targets for the management of liver disease affecting hepatocyte proliferation.
PLoS ONE 08/2014; 9(8):e104449. DOI:10.1371/journal.pone.0104449 · 3.23 Impact Factor
"In addition to these proteins, multiple EZH2 target genes have been shown to be involved in EZH2-mediated cancer aggressiveness. These target genes include stathmin and Wnt antagonists in HCC [122,123]; bone morphogenetic protein receptor 1B in GBM ; p57 in breast and ovarian cancers [124,125]; DAB2IP, SLIT2, TIMP2/3, and CCN3/NOV in prostate cancer [126-129]; FOXC1, HOXC10, and RAD51 in breast cancer [130-132]; CXXC4 in gastric cancer ; MyoD in rhabdomyosarcoma ; rap1GAP in HN cancer ; CASZ1 in neuroblastoma ; and RUNX3 and KLF2 in multiple cancer types [136,137]. In addition, several molecules such as Bim, TRAIL, and FBXO32 play a role in apoptosis induced by the inhibition of EZH2 [138-140]. "
[Show abstract][Hide abstract] ABSTRACT: Polycomb repressive complex 2 (PRC2) is the epigenetic regulator that induces histone H3 lysine 27 methylation (H3K27me3) and silences specific gene transcription. Enhancer of zeste homolog 2 (EZH2) is an enzymatic subunit of PRC2, and evidence shows that EZH2 plays an essential role in cancer initiation, development, progression, metastasis, and drug resistance. EZH2 expression is indeed regulated by various oncogenic transcription factors, tumor suppressor miRNAs, and cancer-associated non-coding RNA. EZH2 activity is also controlled by post-translational modifications, which are deregulated in cancer. The canonical role of EZH2 is gene silencing through H3K27me3, but accumulating evidence shows that EZH2 methlyates substrates other than histone and has methylase-independent functions. These non-canonical functions of EZH2 are shown to play a role in cancer progression. In this review, we summarize current information on the regulation and roles of EZH2 in cancer. We also discuss various therapeutic approaches to targeting EZH2.
Cancer Research and Treatment 07/2014; 46(3):209-222. DOI:10.4143/crt.2014.46.3.209 · 3.32 Impact Factor
"During heterochromatin formation PRC2 offers a binding platform for multiple chromatin-modifying enzymes including HDACs and DNA methyltransferase-1 (DNMT1) (Cheng et al., 2011; Tae et al., 2011; Vire et al., 2006). Methylation of histone H3K9 due to SUV39H1 and G9a activity additionally stablizes heterochromatin structures by tethering the chromodomain-containing adaptor proteins HP1α, -β, and -γ (du Chene et al., 2007). "
[Show abstract][Hide abstract] ABSTRACT: Replication-competent latent HIV-1 proviruses that persist in the genomes of a very small subset of resting memory T cells in infected individuals under life-long antiretroviral therapy present a major barrier towards viral eradication. Multiple molecular mechanisms are required to repress the viral trans-activating factor Tat and disrupt the regulatory Tat feedback circuit leading to the establishment of the latent viral reservoir. In particular, latency is due to a combination of transcriptional silencing of proviruses via host epigenetic mechanisms and restrictions on the expression of P-TEFb, an essential co-factor for Tat. Induction of latent proviruses in the presence of antiretroviral therapy is expected to enable clearance of latently infected cells by viral cytopathic effects and host antiviral immune responses. An in-depth comprehensive understanding of the molecular control of HIV-1 transcription should inform the development of optimal combinatorial reactivation strategies that are intended to purge the latent viral reservoir.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.