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Long noncoding RNA EWSAT1-mediated gene repression facilitates Ewing sarcoma oncogenesis.

Abstract
Chromosomal translocation that results in fusion of the genes encoding RNA-binding protein EWS and transcription factor FLI1 (EWS-FLI1) is pathognomonic for Ewing sarcoma. EWS-FLI1 alters gene expression through mechanisms that are not completely understood. We performed RNA sequencing (RNAseq) analysis on primary pediatric human mesenchymal progenitor cells (pMPCs) expressing EWS-FLI1 in order to identify gene targets of this oncoprotein. We determined that long noncoding RNA-277 (Ewing sarcoma-associated transcript 1 [EWSAT1]) is upregulated by EWS-FLI1 in pMPCs. Inhibition of EWSAT1 expression diminished the ability of Ewing sarcoma cell lines to proliferate and form colonies in soft agar, whereas EWSAT1 inhibition had no effect on other cell types tested. Expression of EWS-FLI1 and EWSAT1 repressed gene expression, and a substantial fraction of targets that were repressed by EWS-FLI1 were also repressed by EWSAT1. Analysis of RNAseq data from primary human Ewing sarcoma further supported a role for EWSAT1 in mediating gene repression. We identified heterogeneous nuclear ribonucleoprotein (HNRNPK) as an RNA-binding protein that interacts with EWSAT1 and found a marked overlap in HNRNPK-repressed genes and those repressed by EWS-FLI1 and EWSAT1, suggesting that HNRNPK participates in EWSAT1-mediated gene repression. Together, our data reveal that EWSAT1 is a downstream target of EWS-FLI1 that facilitates the development of Ewing sarcoma via the repression of target genes.
AuthorsMichelle Marques Howarth, David Simpson, Siu P Ngok, Bethsaida Nieves, Ron Chen, Zurab Siprashvili, Dedeepya Vaka, Marcus R Breese, Brian D Crompton, Gabriela Alexe, Doug S Hawkins, Damon Jacobson, Alayne L Brunner, Robert West, Jaume Mora, Kimberly Stegmaier, Paul Khavari, E Alejandro Sweet-Cordero
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 12 Pg. 5275-90 (Dec 2014) ISSN: 1558-8238 [Electronic] United States
PMID25401475 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • EWS-FLI fusion protein
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • RNA, Long Noncoding
  • RNA, Neoplasm
  • RNA-Binding Protein EWS
  • Ribonucleoproteins
  • HNRNPK protein, human
Topics
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic (genetics, metabolism, pathology)
  • Down-Regulation (genetics)
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Oncogene Proteins, Fusion (biosynthesis, genetics)
  • Proto-Oncogene Protein c-fli-1 (biosynthesis, genetics)
  • RNA, Long Noncoding (biosynthesis, genetics)
  • RNA, Neoplasm (biosynthesis, genetics)
  • RNA-Binding Protein EWS (biosynthesis, genetics)
  • Ribonucleoproteins (genetics, metabolism)
  • Sarcoma, Ewing (genetics, metabolism, pathology)
  • Sequence Analysis, RNA
  • Up-Regulation (genetics)

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