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http://purl.uniprot.org/citations/22570737http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/22570737http://www.w3.org/2000/01/rdf-schema#comment"

Background

Liposarcomas are the most common class of soft tissue sarcomas, and myxoid liposarcoma is the second most common liposarcoma. EWSR1-DDIT3 is a chimeric fusion protein generated by the myxoid liposarcoma-specific chromosomal translocation t(12;22)(q13;q12). Current studies indicate that multipotent mesenchymal cells are the origin of sarcomas. The mechanism whereby EWSR1-DDIT3 contributes to the phenotypic selection of target cells during oncogenic transformation remains to be elucidated.

Methodology/principal findings

Reporter assays showed that the EWSR1-DDIT3 myxoid liposarcoma fusion protein, but not its wild-type counterparts EWSR1 and DDIT3, selectively repressed the transcriptional activity of cell lineage-specific marker genes in multipotent mesenchymal C3H10T1/2 cells. Specifically, the osteoblastic marker Opn promoter and chondrocytic marker Col11a2 promoter were repressed, while the adipocytic marker Ppar-γ2 promoter was not affected. Mutation analyses, transient ChIP assays, and treatment of cells with trichostatin A (a potent inhibitor of histone deacetylases) or 5-Aza-2'-deoxycytidine (a methylation-resistant cytosine homolog) revealed the possible molecular mechanisms underlying the above-mentioned selective transcriptional repression. The first is a genetic action of the EWSR1-DDIT3 fusion protein, which results in binding to the functional C/EBP site within Opn and Col11a2 promoters through interaction of its DNA-binding domain and subsequent interference with endogenous C/EBPβ function. Another possible mechanism is an epigenetic action of EWSR1-DDIT3, which enhances histone deacetylation, DNA methylation, and histone H3K9 trimethylation at the transcriptional repression site. We hypothesize that EWSR1-DDIT3-mediated transcriptional regulation may modulate the target cell lineage through target gene-specific genetic and epigenetic conversions.

Conclusions/significance

This study elucidates the molecular mechanisms underlying EWSR1-DDIT3 fusion protein-mediated phenotypic selection of putative target multipotent mesenchymal cells during myxoid liposarcoma development. A better understanding of this process is fundamental to the elucidation of possible direct lineage reprogramming in oncogenic sarcoma transformation mediated by fusion proteins."xsd:string
http://purl.uniprot.org/citations/22570737http://purl.org/dc/terms/identifier"doi:10.1371/journal.pone.0036682"xsd:string
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/author"Kimura T."xsd:string
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/author"Kanamori M."xsd:string
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/author"Kawaguchi Y."xsd:string
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/author"Suzuki K."xsd:string
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/author"Seki S."xsd:string
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/author"Hori T."xsd:string
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/author"Matsui Y."xsd:string
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/author"Motomura H."xsd:string
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/author"Yahara Y."xsd:string
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/author"Higashimoto M."xsd:string
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/date"2012"xsd:gYear
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/name"PLoS One"xsd:string
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/pages"e36682"xsd:string
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/title"Myxoid liposarcoma-associated EWSR1-DDIT3 selectively represses osteoblastic and chondrocytic transcription in multipotent mesenchymal cells."xsd:string
http://purl.uniprot.org/citations/22570737http://purl.uniprot.org/core/volume"7"xsd:string
http://purl.uniprot.org/citations/22570737http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/22570737
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