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An EBF3-Mediated Transcriptional Program That Induces Cell Cycle Arrest and Apoptosis

Departments of ¹ Anatomy and Cell Biology and ² Biochemistry and Molecular Biology, ³ Program in Cancer Genetics, Epigenetics and Tumor Virology, and ⁴ Program in Signaling, Apoptosis and Cancer, Shands Cancer Center, University of Florida College of Medicine, Gainesville, Florida

Requests for reprints: Daiqing Liao, Department of Anatomy and Cell Biology, Shands Cancer Center, University of Florida College of Medicine, P.O. Box 103633, 1376 Mowry Road, Gainesville, FL 32611-3633. Phone: 352-273-8188; Fax: 352-273-8285; E-mail: dliao{at}ufl.edu.

In a genome-wide screen for putative tumor suppressor genes, the EBF3 locus on the human chromosome 10q26.3 was found to be deleted or methylated in 73% of the examined cases of brain tumors. EBF3 is expressed in normal brain but is silenced in brain tumors. Therefore, it is suggested that EBF3 is a tumor suppressor. However, it remains unknown whether inactivation of EBF3 locus also occurs in other types of tumors and what functions of EBF3 underlie EBF3-mediated tumor suppression. We show here that expression of EBF3 resulted in cell cycle arrest and apoptosis. The expression of cyclin-dependent kinase inhibitors was profoundly affected with early activation and then repression of p21^cip1/waf1 and persistent activation of both p27^kip1 and p57^kip2, whereas genes involved in cell survival and proliferation were suppressed. EBF3 bound directly to p21^cip1/waf1 promoter and regulated transcription from both p21^cip1/waf1 and p27^kip1 promoters in reporter assays. Apoptosis occurred 48 hours after EBF3 expression with caspase-3 activation. Silencing of the EBF3 locus was observed in brain, colorectal, breast, liver, and bone tumor cell lines and its reactivation was achieved on treatment with 5-aza-2'-deoxycytidine and trichostatin A in a significant portion of these tumor cells. Therefore, EBF3 regulates a transcriptional program underlying a putative tumor suppression pathway. (Cancer Res 2006; 66(19): 9445-52)

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