Abstract 2207: Elucidating mechanisms employed by NFIL3 to impact cancer cell survival

Abstract

Abstract NFIL3 was recently identified as a novel modulator of FOXO1 output on the PI3K pathway. NFIL3 bound to DNA to physically block FOXO1 recruitment to genes that induce apoptosis. The diminishment in NFIL3 expression via RNA interference led to FOXO recruitment to cell death genes, an increase in Histone H3 acetylation on these genes, and increased expression of these genes. However, a number of observations suggest that FOXO1 is not the main target of NFIL3 in these cells. First, the NFIL3 and FOXO1 DNA consensus sites have almost no similarity. Second, the loss of FOXO1 or all three FOXO factors failed to suppress the cell death phenotype upon the diminishment of NFIL3 in MEFs. The goal of this project is to identify the factor(s) that NFIL3 directly blocks from DNA recruitment to promote cellular survival. In previous work, the NFIL3 and FOXO1 sites were mapped as being adjacent on the DNA. The mapped NFIL3 site was required for NFIL3 to associate with the DNA in biochemical experiments and for NFIL3 to regulate the promoter sequence in reporter assays. The mapped NFIL3 site is a perfect match for the bZIP transcription factor CCAAT/enhancer binding protein beta (CEBPB) consensus sequence. NFIL3 has been shown to block the ability of CEBPB to activate transcription by competing for access to the same DNA consensus site in numerous contexts including neuronal regeneration, PKA pathway transcriptional programs and the regulation of hepatitis C viral genes. Aside from DBP in circadian rhythm, CEBPB is the most commonly antagonized factor by NFIL3 in the literature. We are investigating if NFIL3 hinders FOXO1 recruitment to cell death genes by directly antagonizing CEBPB recruitment to these genes using cell biological and bioinformatics approaches. We have found that CEBPB is required for efficient induction of a subset of NFIL3 repressed genes. Citation Format: Megan Keniry, Omar Caballero, Itzel Flores, Andrea Salinas. Elucidating mechanisms employed by NFIL3 to impact cancer cell survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2207. doi:10.1158/1538-7445.AM2015-2207