Abstract
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.
Highlights
The early B-cell factors (EBF; known as Olf, COE, or O/E; this family of proteins is hereafter called EBF) are a group of DNAbinding transcription factors with the basic helix-loop-helix domain
We found that EBF3 expression profoundly restricted the growth of several tumor cell lines, including glioblastoma U87 MG, osteosarcoma Saos2, and colon carcinoma HCT116
The adenovirus for wild-type EBF3 (Ad-EBF3)-infected cells started to detach from the culture plate by 48 hours postinfection, and most of the cells were detached with very few attached cells by 96 hours postinfection (Fig. 1A)
Summary
The early B-cell factors (EBF; known as Olf, COE, or O/E; this family of proteins is hereafter called EBF) are a group of DNAbinding transcription factors with the basic helix-loop-helix (bHLH) domain. These factors were discovered in 1993 independently as proteins that are involved in regulating expression of genes in two specific cell types: B lymphocyte [1] and olfactory cell [2]. Current address for S.H. Albert: Department of Biology, University of Louisiana at Lafayette, P.O. Box 42451, Lafayette, LA 70504-2451
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