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EWS/ETS Fusions Activate Telomerase in Ewing’s Tumors

¹ Departments of Oral Pathobiological Science and
² Oral Health Science, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan;
³ Department of Biology, Sapporo Medical University School of Medicine, Sapporo, Japan;
⁴ Department of Obstetrics and Gynecology, Kanazawa University, School of Medicine, Kanazawa, Japan;
⁵ Department of Orthopedic Surgery, Gifu University School of Medicine, Gifu, Japan;
⁶ Department of Molecular Biology, Hokkaido University Graduate School of Pharmaceutical Sciences, Sapporo, Japan;
⁷ Department of Immunology, Osaka City University Graduate School of Medicine, Osaka, Japan; and
⁸ Division of Cancer Pathobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

EWS/ETS is a chimeric protein identified in most Ewing’s sarcomas. Although EWS/ETS has been shown to activate transcription as a transcription factor, the detailed targets of EWS/ETS in transformed cells have not been clarified. Herein, we demonstrate that telomerase is a new target of EWS/ETS fusions. Both telomerase activity and the expression level of telomerase reverse transcriptase (TERT) mRNA were up-regulated in NIH3T3 cells transformed by EWS/E1AF and EWS/FLI1 as well as in two Ewing’s sarcoma cell lines. Luciferase assay using the TERT promoter revealed that EWS/E1AF and EWS/FLI1 function as positive regulators of TERT transcription in an ETS binding site-independent manner. EWS/ETS appeared to be included in the initiation complex of TERT transcription and to cooperate with CREB-binding protein (CBP)/p300. When EWS/FLI1 was knocked down in Ewing’s sarcomas cells by RNA interference, the expression level of TERT mRNA and the telomerase activity were significantly decreased. These findings indicate that EWS/ETS fusion proteins activate human telomerase activity in Ewing’s tumors through up-regulation of TERT gene expression, probably as a transcriptional coactivator.

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