O-GlcNAcylation is involved in the transcriptional activity of EWS-FLI1 in Ewing's sarcoma.

Abstract:

:The oncogene EWS-FLI1 encodes a chimeric transcription factor expressed in Ewing's sarcoma family tumors (ESFTs). EWS-FLI1 target gene expression is thought to drive ESFT pathogenesis and, therefore, inhibition of EWS-FLI1 activity holds high therapeutic promise. As the activity of many transcription factors is regulated by post-translational modifications, we studied the presence of modifications on EWS-FLI1. The immuno-purified fusion-protein was recognized by an antibody specific for O-linked beta-N-acetylglucosaminylation, and bound readily to a phosphoprotein-specific dye. Inhibition of Ser/Thr-specific phophatases increased EWS-FLI1 molecular weight and reduced its O-GlcNAc content, suggesting that phosphorylation and O-GlcNAcylation of EWS-FLI1 interact dynamically. By mutation analysis, O-GlcNAcylation was delineated to Ser/Thr residues of the amino-terminal EWS transcriptional-activation domain. Metabolic inhibition of the hexosamine biosynthetic pathway abrogated O-GlcNAcylation of EWS-FLI1 and interfered specifically with transcriptional activation of the EWS-FLI1 target Id2. These results suggest that drugs modulating glycosylation of EWS-FLI1 interfere functionally with its activity and might, therefore, constitute promising additions to the current ESFT chemotherapy.

journal_name

Oncogene

journal_title

Oncogene

authors

Bachmaier R,Aryee DN,Jug G,Kauer M,Kreppel M,Lee KA,Kovar H

doi

10.1038/onc.2008.484

subject

Has Abstract

pub_date

2009-03-05 00:00:00

pages

1280-4

issue

9

eissn

0950-9232

issn

1476-5594

pii

onc2008484

journal_volume

28

pub_type

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