title: EWS-WT1 oncoprotein activates neuronal reprogramming factor ASCL1 and promotes neural differentiation.
abstract: The oncogenic fusion gene EWS-WT1 is the defining chromosomal translocation in desmoplastic small round-cell 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.
authors.affiliation: Tulane University School of Medicine, Department of Pathology and Laboratory Medicine, New Orleans, Louisiana.
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Tulane University School of Medicine, Department of Pathology and Laboratory Medicine, New Orleans, Louisiana.
authors.forename: Jun Hong
authors.initials: JH
authors.lastname: Park
authors.affiliation: Genomics Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland.
authors.forename: WeiPing
authors.initials: W
authors.lastname: Chen
authors.affiliation: Tulane University School of Medicine, Department of Pathology and Laboratory Medicine, New Orleans, Louisiana.
authors.forename: Soo Im
authors.initials: SI
authors.lastname: Kang
authors.affiliation: Tulane University School of Medicine, Department of Pathology and Laboratory Medicine, New Orleans, Louisiana.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Moroz
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Tulane University School of Medicine, Department of Pathology and Laboratory Medicine, New Orleans, Louisiana. slee30@tulane.edu.
authors.forename: Sean Bong
authors.initials: SB
authors.lastname: Lee
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015514:Oncogene Proteins, Fusion; C065500:ASCL1 protein, human; C106032:EWS1-WT1 fusion protein, human