This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yu, Y. Articles by Merlino, G. Search for Related Content PubMed PubMed Citation Articles by Yu, Y. Articles by Merlino, G.

The Homeoprotein Six1 Transcriptionally Activates Multiple Protumorigenic Genes but Requires Ezrin to Promote Metastasis

¹ Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland and ² Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California

Requests for reprints: Glenn Merlino, Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, NIH, Building 37, Room 5002, Bethesda, MD 20892-4264. Phone: 301-496-4270; Fax: 301-480-7618; E-mail: gmerlino{at}helix.nih.gov.

The vast majority of deaths associated with cancer are a consequence of a complex phenotypic behavior, metastasis, by which tumor cells spread from their primary site of origin to regional and distant sites. This process requires the tumor cell to make numerous adjustments, both subtle and dramatic, to successfully reach, survive, and flourish at favorable secondary sites. It has been suggested that molecular mechanisms accounting for metastatic behavior can recapitulate those employed during embryogenesis. We have shown that the homeodomain transcription factor Six1, known to be required for normal development of migratory myogenic progenitor cells, is sufficient to promote metastatic spread in a mouse model of the pediatric skeletal muscle cancer rhabdomyosarcoma. Here, we report that Six1 is able to activate the expression of a set of protumorigenic genes (encoding cyclin D1, c-Myc, and Ezrin) that can control cell proliferation, survival, and motility. Although the role of Ezrin in cytoskeletal organization and adhesion has been well studied, the means by which its expression is regulated are poorly understood. We now show that the gene encoding Ezrin is a direct transcriptional target of Six1. Moreover, Ezrin is indispensable for Six1-induced metastasis and highly expressed in a panel of representative pediatric cancers. Our data indicate that Ezrin represents a promising therapeutic target for patients with advanced-stage rhabdomyosarcoma and perhaps other malignancies. (Cancer Res 2006; 66(4): 1982-9)

This article has been cited by other articles:

				R. D. Coletta, K. L. Christensen, D. S. Micalizzi, P. Jedlicka, M. Varella-Garcia, and H. L. Ford Six1 Overexpression in Mammary Cells Induces Genomic Instability and Is Sufficient for Malignant Transformation Cancer Res., April 1, 2008; 68(7): 2204 - 2213. [Abstract] [Full Text] [PDF]

				G. Schlosser How old genes make a new head: redeployment of Six and Eya genes during the evolution of vertebrate cranial placodes Integr. Comp. Biol., September 1, 2007; 47(3): 343 - 359. [Abstract] [Full Text] [PDF]

				K. Behbakht, L. Qamar, C. S. Aldridge, R. D. Coletta, S. A. Davidson, A. Thorburn, and H. L. Ford Six1 Overexpression in Ovarian Carcinoma Causes Resistance to TRAIL-Mediated Apoptosis and Is Associated with Poor Survival Cancer Res., April 1, 2007; 67(7): 3036 - 3042. [Abstract] [Full Text] [PDF]

				K. Wu, A. Li, M. Rao, M. Liu, V. Dailey, Y. Yang, D. Di Vizio, C. Wang, M. P. Lisanti, G. Sauter, et al. DACH1 Is a Cell Fate Determination Factor That Inhibits Cyclin D1 and Breast Tumor Growth. Mol. Cell. Biol., October 1, 2006; 26(19): 7116 - 7129. [Abstract] [Full Text] [PDF]