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.