Abstract 2849: RNA-binding protein FXR1 negatively regulates senescence by destabilizing mRNA CDKN1A and stabilizing noncoding RNA telomerase RNA component

RNA-binding proteins (RBPs) regulate numerous aspects of co- and post-transcriptional gene expression. RBP fragile X-related protein 1 (FXR1) belongs to a family of RNA-binding proteins that includes functionally similar Fragile X mental retardation 1 (FMR1) and Fragile X-related 2 (FXR2). FMR1 is significantly studied in Fragile X Syndrome (FXS) where the gene is non-functional due to mutation or aberrant methylation. FXR1 protein is highly expressed in multiple cancers including lung and oral cancers. Here, we demonstrate that RBP FXR1 plays an essential role in the growth of head and neck squamous cell carcinomas (HNSCC) by blocking cellular senescence. FXR1 MEF cells were stained positive for senescence associated beta-galactosidase straining. We report a major function of FXR1 as it promotes the stability of Telomerase RNA Component (TERC), a non-coding RNA and simultaneously destabilizes CDKN1A mRNA, and blocks cellular senescence. FXR1-deficient HNSCC cells show an increase in different cyclin dependent kinase inhibitors (p21, p27), a decrease in p-AKT, and these cells also undergo a G0/G1 cell cycle arrest which are the early onsets of cellular senescence. FXR1 binds and stabilizes TERC RNA for telomere maintenance. On the contrary, FXR1 binds and destabilizes CDKN1A mRNA. By an independent assay we also show that the senescence phenomenon was only observed by a combined up and downregulation of CDKN1A and TERC, respectively which was only obtained by FXR1 knockdown. Thus, FXR1 forms a molecular link between CDKN1A and TERC for cell cycle control and telomere length, respectively, to repress cellular senescence in HNSCC. Citation Format: Mrinmoyee Majumder, Nallasivam Palanisamy, Shuo Qie, Terry Day, Alan J. Diehl, Viswanathan Palanisamy. RNA-binding protein FXR1 negatively regulates senescence by destabilizing mRNA CDKN1A and stabilizing noncoding RNA telomerase RNA component. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2849.