RNA-Binding Protein FXR1 Regulates p21 and TERC RNA to Bypass p53-Mediated Cellular Senescence in OSCC
Autor: | Terrence A. Day, Shuo Qie, Reniqua House, Viswanathan Palanisamy, David M. Neskey, Nallasivam Palanisamy, J. Alan Diehl, Mrinmoyee Majumder |
---|---|
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Viral Diseases Aging Telomerase Cancer Research Carcinogenesis Physiology Gene Expression Squamous Cell Lung Carcinoma RNA-binding proteins RNA-binding protein Biochemistry Lung and Intrathoracic Tumors Gene expression Medicine and Health Sciences Cell Cycle and Cell Division Cellular Senescence Genetics (clinical) Cellular Stress Responses Staining Cell Staining Squamous Cell Carcinomas Head and Neck Tumors Enzymes 3. Good health Infectious Diseases Oncology Cell Processes Perspective Carcinoma Squamous Cell Mouth Neoplasms Oxidoreductases Luciferase Protein Binding Research Article Cyclin-Dependent Kinase Inhibitor p21 Senescence Human Papillomavirus Infection lcsh:QH426-470 Urology Sexually Transmitted Diseases Biology Research and Analysis Methods Transfection Carcinomas 03 medical and health sciences Telomerase RNA component Head and Neck Squamous Cell Carcinoma Cell Line Tumor Genetics Humans Gene silencing Molecular Biology Techniques Molecular Biology Ecology Evolution Behavior and Systematics Messenger RNA Biology and life sciences Genitourinary Infections Proteins Cancers and Neoplasms RNA Correction Cell Biology lcsh:Genetics 030104 developmental biology Specimen Preparation and Treatment Enzymology Cancer research Tumor Suppressor Protein p53 Physiological Processes Organism Development DNA Damage Developmental Biology |
Zdroj: | PLoS Genetics, Vol 12, Iss 10, p e1006411 (2016) PLoS Genetics, Vol 12, Iss 9, p e1006306 (2016) PLoS Genetics |
ISSN: | 1553-7404 |
Popis: | 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. Author Summary Understanding the mechanisms underlying evasion of cellular senescence in tumor cells is expected to provide better treatment outcomes. Here, we identify RNA-binding proteins FXR1 (Fragile X-Related protein 1), that is overexpressed in oral cancer tissues and cells bypasses cellular senescence through p53/p21-dependent manner. Once FXR1 is amplified in oral cancer cells, protein p21 is suppressed and non-coding RNA TERC expression is aided, resulting in reduction of cellular senescence and promotion of cancer growth. Here, we demonstrate the importance of FXR1 in antagonizing tumor cell senescence using human head and neck tumor tissues and multiple oral cancer cells including the cells expressing p53 wild-type and mutants. This finding is important as FXR1/TERC overexpression is associated with proliferation of HNSCC and poor prognosis, pointing to possible stratification of HNSCC patients for therapies. |
Databáze: | OpenAIRE |
Externí odkaz: |