<i>TP53</i> Genomic Status Regulates Sensitivity of Gastric Cancer Cells to the Histone Methylation Inhibitor 3-Deazaneplanocin A (DZNep)

Cheng, Lee; Itahana, Yoko; Lei, Zheng Deng; Chia, Na‐Yu; Wu, Yonghui; Yu, Yiping; Zhang, Shen Li; Thike, Aye Aye; Pandey, Anuradha; Rozen, Steve; Voorhoeve, P. Mathijs; Yu, Qiang; Tan, Puay Hoon; Bay, Boon Huat; Itahana, Koji; Tan, Patrick

doi:10.1158/1078-0432.ccr-12-0036

Cited by 70 publications

(57 citation statements)

References 48 publications

(66 reference statements)

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“…Importantly, both treatments resulted in a marked decrease in global levels of H3K27me3 (Figure 6b), as previously reported, 25,40,41 whereas the levels of H3K9me3, another repressive mark, remained unchanged demonstrating that they act mainly through inhibition of EZH2-containing complexes at the used doses on the basis of previous reports for DZNep. 24,40,[42][43][44][45] Consistently with EZH2 silencingdependent effects, the appearance of apoptotic Annexin V-positive cells was seen in both DZNep-and MC1945-treated RH30 cells ( Figure 6c) associated with transcriptional upregulation of FBXO32 gene and decreased Myogenin levels after 72 h (Figure 6d). Collectively, these observations indicate that pharmacological approaches either favoring the degradation or blocking the catalytic functions of EZH2 affect the proliferative potential of PAX3-FOXO1-positive alveolar RMS cells and mirror the effect of siRNA-and short hairpin RNAmediated EZH2 depletion in derepressing FBXO32.…”

Section: Fbxo32 Is Directly Targeted By Ezh2 In Pax3-foxo1 Alveolar Rsupporting

confidence: 59%

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

et al. 2013

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The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS.Oncogene ( Keywords: EZH2; FBXO32; histone methyltransferases; PAX3-FOXO1; rhabdomyosarcoma; Polycomb proteins INTRODUCTION Rhabdomyosarcomas (RMS) are heterogeneous highly malignant tumors, which account for 7-8% of all pediatric malignancies and over half of the soft-tissue sarcomas in children. RMS are classically subdivided in two major histotypes: embryonal (around 70-80%) and alveolar (around 20-30%), the latter often metastatic at diagnosis and showing a high risk of recurrence. 1 In 70% of cases, alveolar RMS is characterized by the chromosomal translocation t(2;13) or t(1;13), resulting in

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Section: Fbxo32 Is Directly Targeted By Ezh2 In Pax3-foxo1 Alveolar Rsupporting

confidence: 59%

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

et al. 2013

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“…Despite a substantially declining incidence of gastric cancer (GC), it still is one of the most frequent malignancies worldwide accounting for 700,000 deaths annually [1]. The carcinogenesis of GC is complicated, and most patients experienced asymptomatic presentation in the early stage, resulting metastases at diagnosis.…”

Section: Introductionmentioning

confidence: 99%

MiR-19a promotes epithelial-mesenchymal transition through PI3K/AKT pathway in gastric cancer

Lü

Zuo

et al. 2015

WJG

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It has been reported that miR-19a was up-regulated in gastric cancer (GC), playing an oncogenic role. However, the underlying mechanism is still unknown. Therefore, in our present study, we investigated the role of miR-19a in gastric tissues as well as 2 GC cell lines. In vivo in clinical tissue level, we have detected basal expression level of miR-19a using real-time reversal transcriptional PCR (RT-PCR); in addition, the relevance between expression of miR-19a and clinic-pathological information was also analyzed. In vitro in cell line level, miR-19a was ectopically expressed using over expression and knock-down strategy. It was found that the overexpression of miR19a was significantly associated with metastasis of GC and inferior overall prognosis on clinical tissue level; that promotes the proliferation, migration and invasion; and that overexpression of miR-19a can promote the epithelialmesenchymal transition through activating PI3K/AKT pathway. Blocking the PI3K/AKT pathway could cancel the effect of miR-19a. All together, our results suggest that miR-19a could be used as a promising therapeutic target in the treatment of GC.

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“…p53 genomic status is therefore a potential predictive marker of DZNep response in this specific cell type [213].…”

Section: Discussionmentioning

confidence: 99%

Role of Enhancer of Zeste Homolog 2 Polycomb Protein and Its Significance in Tumor Progression and Cell Differentiation

Marchesi¹,

Bagella²

2013

Chromatin Remodelling

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TP53 Genomic Status Regulates Sensitivity of Gastric Cancer Cells to the Histone Methylation Inhibitor 3-Deazaneplanocin A (DZNep)

Cited by 70 publications

References 48 publications

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

MiR-19a promotes epithelial-mesenchymal transition through PI3K/AKT pathway in gastric cancer

Role of Enhancer of Zeste Homolog 2 Polycomb Protein and Its Significance in Tumor Progression and Cell Differentiation

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