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
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