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J. Biol. Chem., Vol. 282, Issue 18, 13316-13325, May 4, 2007

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Leptin-induced Growth Stimulation of Breast Cancer Cells Involves Recruitment of Histone Acetyltransferases and Mediator Complex to CYCLIN D1 Promoter via Activation of Stat3^*

Neeraj K. Saxena, Paula M. Vertino^¶, Frank A. Anania, and Dipali Sharma^¶1

From the Division of Digestive Diseases, Departments of Medicine and Radiation Oncology, ^¶Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322

Numerous epidemiological studies documented that obesity is a risk factor for breast cancer development in postmenopausal women. Leptin, the key player in the regulation of energy balance and body weight control also acts as a growth factor on certain organs in both normal and disease state. In this study, we analyzed the role of leptin and the molecular mechanism(s) underlying its action in breast cancer cells that express both short and long isoforms of leptin receptor. Leptin increased MCF7 cell population in the S-phase of the cell cycle along with a robust increase in CYCLIN D1 expression. Also, leptin induced Stat3-phosphorylation-dependent proliferation of MCF7 cells as blocking Stat3 phosphorylation with a specific inhibitor, AG490, abolished leptin-induced proliferation. Using deletion constructs of CYCLIN D1 promoter and chromatin immunoprecipitation assay, we show that leptin induced increase in CYCLIN D1 promoter activity is mediated through binding of activated Stat3 at the Stat binding sites and changes in histone acetylation and methylation. We also show specific involvement of coactivator molecules, histone acetyltransferase SRC1, and mediator complex in leptin-mediated regulation of CYCLIN D1 promoter. Importantly, silencing of SRC1 and Med1 abolished the leptin induced increase in CYCLIN D1 expression and MCF7 cell proliferation. Intriguingly, recruitment of both SRC1 and Med1 was dependent on phosphorylated Stat3 as AG490 treatment inhibited leptin-induced recruitment of these coactivators to CYCLIN D1 promoter. Our data suggest that CYCLIN D1 may be a target gene for leptin mediated growth stimulation of breast cancer cells and molecular mechanisms involve activated Stat3-mediated recruitment of distinct coactivator complexes.

Received for publication, October 17, 2006 , and in revised form, February 16, 2007.

^* This work was supported by United States Army Medical Research and Material Command Grant BC-030963 and Susan G. Komen Research Foundation Grant BCTR 0503526 (to D. S.) and National Institutes of Health Grants AA 12933 and DK 062092 (to F. A. A.). 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.

¹ To whom correspondence should be addressed: 1701 Uppergate Dr., Atlanta, GA 30322. Tel.: 404-778-3265; Fax: 404-778-5530; E-mail: dsharma{at}emory.edu.

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