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J. Biol. Chem., Vol. 283, Issue 21, 14665-14673, May 23, 2008

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Twist Is Transcriptionally Induced by Activation of STAT3 and Mediates STAT3 Oncogenic Function^*

George Z. Cheng¹, WeiZhou Zhang¹², Mei Sun, Qi Wang, Domenico Coppola, Mena Mansour, LiMei Xu, Carliann Costanzo, Jin Q. Cheng, and Lu-Hai Wang³

From the Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029 and the Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612

To explore the basis of metastasis, we compared the human breast cancer lines MCF-7 and MDA-MB453, which have low invasive ability, with their sublines MCF7-I4 and MDA-MB453-I4 with high invasive ability for gene expression and signaling pathways. We previously showed that the I4 lines had dramatically elevated levels of Twist compared with their parental lines. In this study, we observed significantly increased STAT3 Tyr⁷⁰⁵ phosphorylation, but not the STAT3 protein levels, in the I4 lines. Activation of STAT3 by interleukin-6 or expression of activated Src induced Twist expression at protein and mRNA levels. Inhibiting STAT3 by a small molecule inhibitor, JSI-124, STAT3 small hairpin RNAs, or dominant negative STAT3 resulted in significant reduction of Twist protein and mRNA expression. STAT3 directly bound to the second proximal STAT3-binding site on the human Twist promoter and activated its transcriptional activity. Inhibition of STAT3 reduced migration, invasion, and colony formation of the I4 cells. Ectopic expression of Twist significantly rescued those phenotypes. Ten normal and 46 tumor specimens of breast tissues were examined for activation of STAT3 and expression of Twist. There was a strong correlation between Tyr⁷⁰⁵ p-STAT3 and Twist level in the late stage tumor tissues. Our results indicate that activated STAT3 transcriptionally induces Twist, which plays an important role in promoting migration, invasion, and anchorage-independent growth. Together with our previous observation that Twist transcriptionally induces AKT2 to mediate Twist-promoted oncogenic functions, we conclude that STAT3, Twist, and AKT2 form a functional signaling axis to regulate pivotal oncogenic properties of cancer cells.

Received for publication, September 5, 2007 , and in revised form, March 19, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants CA29339 (to L.-H. W.) and CA107078 (to J. Q. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ These authors contributed equally to this work.

² Supported in part by Fellowship C021334 from New York State Department of Health.

³ To whom correspondence should be addressed: Dept. of Microbiology, One Gustave L. Levy Place, Box 1124, New York, NY 10029-6574. Tel.: 212-241-3759; Fax: 212-534-1684; E-mail: lu-hai.wang{at}mssm.edu.

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