RNA-Binding Protein FXR1 Regulates p21 and TERC RNA to Bypass p53-Mediated Cellular Senescence in OSCC.
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.
Department of Oral Health Sciences and Center for Oral Health Research, College of Dental Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Mrinmoyee
M
Majumder
Department of Oral Health Sciences and Center for Oral Health Research, College of Dental Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Reniqua
R
House
Department of Urology, Henry Ford Health System, Vattikuti Urology Institute, Detroit, Michigan, United States of America.
Nallasivam
N
Palanisamy
Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Shuo
S
Qie
Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Terrence A
TA
Day
Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
David
D
Neskey
Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
J Alan
JA
Diehl
Department of Oral Health Sciences and Center for Oral Health Research, College of Dental Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.|Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Viswanathan
0000-0001-5128-2878
V
Palanisamy
D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D009062:Mouth Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; C096916:FXR1 protein, human; D016601:RNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase