Pharmacologic inhibition of epigenetic modification reveals targets of aberrant promoter methylation in ewing sarcoma. Issue 9 (18th March 2013)

• Record Type: Journal Article
• Authors: Nestheide, Shawnagay; Bridge, Julia A.; Barnes, Michael; Frayer, Robert; Sumegi, Janos
• Is Part Of: Pediatric blood & cancer. Volume 60:Issue 9(2013:Sep.)
• Page Start: 1437
• Page End: 1446
• Publication Date: 2013-03-18
• Subjects: Tumors in children -- Periodicals; Blood -- Diseases -- Periodicals; Cancer in children -- Periodicals; 618.92
• DOI: 10.1002/pbc.24526
• Languages: English
• ISSNs: 1545-5009

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="pbc24526-sec-0001" sec-type="section"> <title>Background</title> <p>Ewing sarcoma (ES), a highly aggressive tumor of children and young adults, is characterized most commonly by an 11;22 chromosomal translocation that fuses <italic>EWSR1</italic> located at 22q12 with <italic>FLI1</italic>, coding for a member of the ETS family of transcription factors. Although genetic changes in ES have been extensively researched, our understanding of the role of epigenetic modifications in this neoplasm is limited.</p> </sec> <sec id="pbc24526-sec-0002" sec-type="section"> <title>Procedure</title> <p>In an effort to improve our knowledge in the role of epigenetic changes in ES we evaluated the <italic>in vitro</italic> antineoplastic effect of the DNA methyltransferase inhibitor 5‐Aza‐deoxycytidine (5‐Aza‐dC) and identified epigenetically silenced genes by pharmacologic unmasking of DNA methylation coupled with genome‐wide expression profiling.</p> </sec> <sec id="pbc24526-sec-0003" sec-type="section"> <title>Results</title> <p>Comparisons between untreated and 5‐Aza‐dC treated ES cell lines (n = 5) identified 208 probe sets with at least twofold difference in expression (<italic>P</italic> ≤ 0.05). The 208 probe sets represented 145 upregulated and 31 down‐regulated genes. Of the 145 genes upregulated after 5‐Aza‐dC treatment, four: were further characterized. <italic>ACRC</italic>, <italic>CLU</italic>, <italic>MEST</italic>, and <italic>NNAT</italic> were found to be hypermethylated and transcriptionally down‐regulated in ES cell lines. Further studies revealed that <italic>ACRC</italic>, <italic>CLU</italic>, <italic>MEST</italic>, and <italic>NNAT</italic> were often hypermethylated in primary ES tumors. Transfection‐mediated reexpression of <italic>ACRC</italic>, <italic>CLU</italic>, <italic>MEST</italic>, and <italic>NNAT</italic> in ES cell lines resulted in decreased growth in culture.</p> </sec> <sec id="pbc24526-sec-0004" sec-type="section"> <title>Conclusions</title> <p>This study demonstrated epigenetically modified genes in ES cell lines and primary tumors and suggested that epigenetic dysregulation may contribute to disease pathogenesis in ES. Pediatr Blood Cancer 2013;60:1437–1446. © 2013 Wiley Periodicals, Inc.</p> </sec> </abstract>