Abstract 3159: ZAR2 transcriptionally represses the ATPase ATP6V0A4 to negatively regulate invasiveness of breast cancer cells

Abstract

Abstract ZAR2 is a recently characterized RNA-dependent transcriptional repressor protein that is implicated in the cell cycle-dependent regulation of BRCA2 gene expression. We have shown previously that ZAR2 mRNA is transcribed from the overlapping bi-directional promoter of the BRCA2 gene, binds to the overlapping promoter and prevents the expression of BRCA2 through chromatin remodeling. ZAR2 level is significantly low in the invasive breast cancer cells and tissues as compared to the non-invasive cells. Knockdown of ZAR2 in the non-invasive breast cancer cells increased the in vitro invasiveness of these cells whereas forced expression of ZAR2 in the invasive breast cancer cells prevented their invasiveness. To understand the possible mechanism of ZAR2-mediated regulation of invasiveness of the breast cancer cells we studied differential gene expression in the ZAR2 knocked down non-invasive breast cancer cells by RNA-seq analysis. One of the genes that are significantly elevated in the ZAR2 knocked down cells is the invasion determining enzyme ATP6V0A4. ATP6V0A4 is transcribed from an overlapping bi-directional promoter along with its partner TMEM213 in the breast cancer cells. We found that both ATP6V0A4 and TMEM213 levels are increased in the ZAR2 knocked down cells whereas cells with forced expression of ZAR2 have a significant decrease in the levels of these proteins. ZAR2 cell cycle dependently binds to the ATP6V0A4/TMEM213 gene promoter to repress the activity of this bi-directional promoter. This study thus reports a new pathway for the regulation of the invasiveness of breast cancer cells. Supported in part by DOD grants BC990678 and BC050641 to GC and NIH grant 1U54RR026140 to SM. Citation Format: Smita Misra, Gautam Chaudhuri. ZAR2 transcriptionally represses the ATPase ATP6V0A4 to negatively regulate invasiveness of breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3159. doi:10.1158/1538-7445.AM2014-3159