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

Abstract

<div>Abstract<p>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<sup>cip1/waf1</sup> and persistent activation of both p27<sup>kip1</sup> and p57<sup>kip2</sup>, whereas genes involved in cell survival and proliferation were suppressed. EBF3 bound directly to p21<sup>cip1/waf1</sup> promoter and regulated transcription from both p21<sup>cip1/waf1</sup> and p27<sup>kip1</sup> 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)</p></div>