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[Cancer Research 63, 8338-8344, December 1, 2003]
© 2003 American Association for Cancer Research


Regular Articles

EWS/ETS Fusions Activate Telomerase in Ewing’s Tumors

Akiko Takahashi1, Fumihiro Higashino1, Mariko Aoyagi1, Koichi Yoshida3, Miyuki Itoh3, Satoru Kyo4, Takatoshi Ohno5, Takahiro Taira6, Hiroyoshi Ariga6, Kohichi Nakajima7, Mitsutoki Hatta1, Masanobu Kobayashi8, Hidehiko Sano2, Takao Kohgo1 and Masanobu Shindoh1

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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H. Guan, Z. Zhou, G. E. Gallick, S.-F. Jia, J. Morales, A. K. Sood, S. J. Corey, and E. S. Kleinerman
Targeting Lyn inhibits tumor growth and metastasis in Ewing's sarcoma
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J. DWYER, H. LI, D. XU, and J.-P. LIU
Transcriptional Regulation of Telomerase Activity: Roles of the the Ets Transcription Factor Family
Ann. N.Y. Acad. Sci., October 1, 2007; 1114(1): 36 - 47.
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Copyright © 2003 by the American Association for Cancer Research.