RNA-Binding Protein FXR1 Regulates p21 and TERC RNA to Bypass p53-Mediated Cellular Senescence in OSCC

• Published in: PLoS genetics 2016-09, Vol.12 (9), p.e1006306
• Main Authors: Majumder, Mrinmoyee, House, Reniqua, Palanisamy, Nallasivam, Qie, Shuo, Day, Terrence A, Neskey, David, Diehl, J Alan, Palanisamy, Viswanathan
• Format: Article
• Language: English
• Subjects: Aging (Biology); Apoptosis; Binding proteins; Biology and Life Sciences; Carcinoma, Squamous Cell - metabolism; Cell Line, Tumor; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Dentistry; Deoxyribonucleic acid; DNA; DNA Damage; Funding; Gene expression; Genetic aspects; Health sciences; Humans; Kinases; Medical research; Medicine; Medicine and Health Sciences; Methods; Molecular biology; Mouth Neoplasms - metabolism; Oral cancer; Otolaryngology; Physiological aspects; Protein Binding; Proteins; Research and Analysis Methods; RNA - genetics; RNA - metabolism; RNA sequencing; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Senescence; Studies; Telomerase; Telomerase - genetics; Telomerase - metabolism; Tumor Suppressor Protein p53 - metabolism; Urology
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006306

RNA-binding proteins (RBP) regulate numerous aspects of co- and post-transcriptional gene expression in cancer cells. Here, we demonstrate that RBP, fragile X-related protein 1 (FXR1), plays an essential role in cellular senescence by utilizing mRNA turnover pathway. We report that overexpressed FXR1 in head and neck squamous cell carcinoma targets (G-quadruplex (G4) RNA structure within) both mRNA encoding p21 (Cyclin-Dependent Kinase Inhibitor 1A (CDKN1A, Cip1) and the non-coding RNA Telomerase RNA Component (TERC), and regulates their turnover to avoid senescence. Silencing of FXR1 in cancer cells triggers the activation of Cyclin-Dependent Kinase Inhibitors, p53, increases DNA damage, and ultimately, cellular senescence. Overexpressed FXR1 binds and destabilizes p21 mRNA, subsequently reduces p21 protein expression in oral cancer cells. In addition, FXR1 also binds and stabilizes TERC RNA and suppresses the cellular senescence possibly through telomerase activity. Finally, we report that FXR1-regulated senescence is irreversible and FXR1-depleted cells fail to form colonies to re-enter cellular proliferation. Collectively, FXR1 displays a novel mechanism of controlling the expression of p21 through p53-dependent manner to bypass cellular senescence in oral cancer cells.