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ALDH1A1 Is a Novel EZH2 Target Gene in Epithelial Ovarian Cancer Identified by Genome-Wide Approaches

Women's Cancer Program and Epigenetics and Progenitor Cell Keystone Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Cancer Prevention Research (Impact Factor: 5.27). 12/2011; 5(3):484-91. DOI: 10.1158/1940-6207.CAPR-11-0414
Source: PubMed

ABSTRACT Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy in the United States. EZH2 silences gene expression through trimethylating lysine 27 on histone H3 (H3K27Me3). EZH2 is often overexpressed in EOC and has been suggested as a target for EOC intervention. However, EZH2 target genes in EOC remain poorly understood. Here, we mapped the genomic loci occupied by EZH2/H3K27Me3 using chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) and globally profiled gene expression in EZH2-knockdown EOC cells. Cross-examination of gene expression and ChIP-seq revealed a list of 60 EZH2 direct target genes whose expression was upregulated more than 1.5-fold upon EZH2 knockdown. For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci. Furthermore, the presence of H3K27Me3 at the genomic loci of these EZH2 target genes was dependent upon EZH2. Interestingly, expression of ALDH1A1, a putative marker for EOC stem cells, was significantly downregulated in high-grade serous EOC (n = 53) compared with ovarian surface epithelial cells (n = 10, P < 0.001). Notably, expression of ALDH1A1 negatively correlated with expression of EZH2 (n = 63, Spearman r = -0.41, P < 0.001). Thus, we identified a list of 60 EZH2 target genes and established that ALDH1A1 is a novel EZH2 target gene in EOC cells. Our results suggest a role for EZH2 in regulating EOC stem cell equilibrium via regulation of ALDH1A1 expression.

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    • "Recently, EZH2 siRNA was reported to induce G2/M arrest in human lung cancer cells [21]. This suggests that the biological function of EZH2 is diverse in different cancer cells, EZH2 mediates histone methylation and recruits DNA methyltransferase in the silencing of a variety of genes, associated with cell cycle control, survival, and other malignant phenotypes [22] [23] [24]. In breast and prostate cancers, EZH2 negatively regulated the tumor suppressor RKIP transcription through repression-associated histone modifications , therefore promoting tumor progression and metastasis [25]. "
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    • "Thus, there is a continuing demand for a potent therapeutic approach to target the majority of human epithelial cancers in which EZH2 is often overexpressed but not mutated. Although a variety of EZH2 target genes have been identified in various cancers (Cao et al., 2008; Kodach et al., 2010; Li et al., 2012; Yu et al., 2007, 2010), a whole-genome analysis indicated that EZH2-silenced genes appear to be moving targets and vary from cancer to cancer (Kondo et al., 2008). An EZH2 target common to multiple cancers with both functional and therapeutic implications has not been described to date. "
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    ABSTRACT: Although small-molecule targeting of EZH2 appears to be effective in lymphomas carrying EZH2 activating mutations, finding similar approaches to target EZH2-overexpressing epithelial tumors remains challenging. In MYC-driven, but not PI3K-driven prostate cancer, we show that interferon-γ receptor 1 (IFNGR1) is directly repressed by EZH2 in a MYC-dependent manner and is downregulated in a subset of metastatic prostate cancers. EZH2 knockdown restored the expression of IFNGR1 and, when combined with IFN-γ treatment, led to strong activation of IFN-JAK-STAT1 tumor-suppressor signaling and robust apoptosis. Pharmacologic depletion of EZH2 by the histone-methylation inhibitor DZNep mimicked the effects of EZH2 knockdown on IFNGR1 induction and delivered a remarkable synergistic antitumor effect with IFN-γ. In contrast, although they efficiently depleted histone Lysine 27 trimethylation, EZH2 catalytic inhibitors failed to mimic EZH2 depletion. Thus, EZH2-inactivated IFN signaling may represent a therapeutic target, and patients with advanced prostate cancer driven by MYC may benefit from the combination of EZH2 and IFN-γ-targeted therapy.
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    • "This is consistent with the observation that histone deacetylase (Van der Vlag and Otte, 1999) and DNA methylation (Nakamura et al., 2008) also regulate the expression of EZH2 target genes. In addition to VASH1, the cellular networks enriched by EZH2 target genes in EOC cells include cell death, growth and proliferation and reproductive system development, and cancer (Li et al., 2012a). These findings further support EZH2's proliferation-promoting and apoptosis-suppressing function. "
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