EWS/FLI1 Oncogene Activates Caspase 3 Transcription and Triggers Apoptosis <i>In vivo</i>

Sohn, Eun Jung; Li, Hongjie; Reidy, Karen T.; Beers, Lisa F.; Christensen, Barbara L.; Lee, Sean Bong

doi:10.1158/0008-5472.can-09-1993

Cited by 46 publications

(57 citation statements)

References 39 publications

(66 reference statements)

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“…As we know, function of caspase-3 on its substrates relied on both the form activation and adequate amount. However, previous studies have given evidence that upregulation of the procaspase-3 could lead to the induction of apoptosis factor activation and thus trigger apoptosis, consistent with our results (19,27,31,32).…”

Section: Discussionsupporting

confidence: 92%

A Novel Plant Homeodomain Finger 10–Mediated Antiapoptotic Mechanism Involving Repression of Caspase-3 in Gastric Cancer Cells

Wei¹,

Liu²,

Li³

et al. 2010

Molecular Cancer Therapeutics

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The mechanisms governing tumorigenesis of gastric cancer have been an area of intense investigation. Currently, plant homeodomain (PHD) finger (PHF) proteins have been implicated in both tumor suppression and progression. However, the function of PHF10 has not been well characterized. Here, we show that various levels of PHF10 protein were observed in gastric cancer cell lines. Alteration of PHF10 expression, which is associated with tumor cell growth, may result in apoptosis in gastric cancer cells both in vitro and in vivo. Knockdown of PHF10 expression in gastric cancer cells led to significant induction of caspase-3 expression at both the RNA and protein levels and thus induced alteration of caspase-3 substrates in a time-dependent manner. Moreover, results from luciferase assays indicated that PHF10 acted as a transcriptional repressor when the two PHD domains contained in PHF10 were intact. Combined with previous findings, our data suggest that PHF10 transcriptionally regulates the expression of caspase-3. Finally, by using systematic reporter deletion and chromatin immunoprecipitation assays, we localized a region between nucleotides −270 and −170 in the caspase-3 promoter that was required for the efficient inhibition of caspase-3 promoter activity by PHF10. Collectively, our findings show that PHF10 repressed caspase-3 expression and impaired the programmed cell death pathway in human gastric cancer at the transcriptional level.

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Section: Discussionsupporting

confidence: 92%

A Novel Plant Homeodomain Finger 10–Mediated Antiapoptotic Mechanism Involving Repression of Caspase-3 in Gastric Cancer Cells

Wei¹,

Liu²,

Li³

et al. 2010

Molecular Cancer Therapeutics

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“…Selection of a PTHLH-expressing cellular fraction in eSZ enabled us to obtain substantially higher efficiency and greater specificity and consistency of tumor formation than previously reported investigations using bone marrow-derived mesenchymal stem/progenitor cells (9,10). In addition, EWS-FLI1 expression induced apoptosis and growth arrest in several cell types, including embryonic fibroblasts (46,47). These data indicate that induction of Ewing's sarcoma by EWS-ETS fusion genes is much more effective for progenitor cells of a certain cell lineage, including the osteochondrogenic axis, especially in developing bone.…”

Section: Discussionmentioning

confidence: 98%

Ewing’s sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors

Tanaka¹,

Yamazaki²,

Kanno³

et al. 2014

J. Clin. Invest.

111

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Ewing's sarcoma is a highly malignant bone tumor found in children and adolescents, and the origin of this malignancy is not well understood. Here, we introduced a Ewing's sarcoma-associated genetic fusion of the genes encoding the RNA-binding protein EWS and the transcription factor ETS (EWS-ETS) into a fraction of cells enriched for osteochondrogenic progenitors derived from the embryonic superficial zone (eSZ) of long bones collected from late gestational murine embryos. EWS-ETS fusions efficiently induced Ewing's sarcoma-like small round cell sarcoma formation by these cells. Analysis of the eSZ revealed a fraction of a precursor cells that express growth/differentiation factor 5 (Gdf5), the transcription factor Erg, and parathyroid hormone-like hormone (Pthlh), and selection of the Pthlh-positive fraction alone further enhanced EWS-ETSdependent tumor induction. Genes downstream of the EWS-ETS fusion protein were quite transcriptionally active in eSZ cells, especially in regions in which the chromatin structure of the ETS-responsive locus was open. Inhibition of β-catenin, poly (ADP-ribose) polymerase 1 (PARP1), or enhancer of zeste homolog 2 (EZH2) suppressed cell growth in a murine model of Ewing's sarcoma, suggesting the utility of the current system as a preclinical model. These results indicate that eSZ cells are highly enriched in precursors to Ewing's sarcoma and provide clues to the histogenesis of Ewing's sarcoma in bone.

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“…To generate a conditional EWS-WT1 mouse, we followed the strategy that was used to generate a conditional EWS-FLI1 mouse (25). Briefly, we inserted a loxP-flanked transcriptional "STOP" cassette (26) in an antisense direction into Ews intron 6 (Fig.…”

Section: Generation Of Ews-wt1 Knockin Mice and Animal Carementioning

confidence: 99%

EWS–WT1 Oncoprotein Activates Neuronal Reprogramming Factor ASCL1 and Promotes Neural Differentiation

et al. 2014

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The oncogenic fusion gene EWS-WT1 is the defining chromosomal translocation in desmoplastic small roundcell tumors (DSRCT), a rare but aggressive soft tissue sarcoma with a high rate of mortality. EWS-WT1 functions as an aberrant transcription factor that drives tumorigenesis, but the mechanistic basis for its pathogenic activity is not well understood. To address this question, we created a transgenic mouse strain that permits physiologic expression of EWS-WT1 under the native murine Ews promoter. EWS-WT1 expression led to a dramatic induction of many neuronal genes in embryonic fibroblasts and primary DSRCT, most notably the neural reprogramming factor ASCL1. Mechanistic analyses demonstrated that EWS-WT1 directly bound the proximal promoter of ASCL1, activating its transcription through multiple WT1-responsive elements. Conversely, EWS-WT1 silencing in DSRCT cells reduced ASCL1 expression and cell viability. Notably, exposure of DSRCT cells to neuronal induction media increased neural gene expression and induced neurite-like projections, both of which were abrogated by silencing EWS-WT1. Taken together, our findings reveal that EWS-WT1 can activate neural gene expression and direct partial neural differentiation via ASCL1, suggesting agents that promote neural differentiation might offer a novel therapeutic approach to treat DSRCT. Cancer Res; 74(16); 4526-35. Ó2014 AACR.

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EWS/FLI1 Oncogene Activates Caspase 3 Transcription and Triggers Apoptosis In vivo

Cited by 46 publications

References 39 publications

A Novel Plant Homeodomain Finger 10–Mediated Antiapoptotic Mechanism Involving Repression of Caspase-3 in Gastric Cancer Cells

A Novel Plant Homeodomain Finger 10–Mediated Antiapoptotic Mechanism Involving Repression of Caspase-3 in Gastric Cancer Cells

Ewing’s sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors

EWS–WT1 Oncoprotein Activates Neuronal Reprogramming Factor ASCL1 and Promotes Neural Differentiation

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