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

Abstract

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.

3q26‐29 Amplification in head and neck squamous cell carcinoma: a review of established and prospective oncogenes

“…However, TP53 is frequently mutated in the disease, allowing tumour cells to escape cell cycle arrest and continue proliferating , which can also lead to increased resistance to chemo‐ and radiotherapy . FXR1 may support this evasion of arrest through negative regulation and/or destabilisation of p21 and stabilisation of telomerase RNA component (TERC) activity in vitro .…”

Regulation of FXR1 by alternative splicing is required for muscle development and controls liquid-like condensates in muscle cells

“…FXR1 is hypothesized to regulate mRNA translation, localization, and stability (Cook et al, 2014;Davidovic et al, 2013;Majumder et al, 2016;Mientjes et al, 2004;Patzlaff et al, 2017;Vasudevan and Steitz, 2007;Zarnescu and Gregorio, 2013); however, there is little known about the mechanisms of function of FXR1 in physiological or pathological contexts. Here, we show quantitative differences in FXR1 isoforms arising from tissue-specific and developmentally regulated alternative splicing and a functional role for fxr1 splicing in myotube formation and Xenopus development.…”

The Rise of FXR1: Escaping Cellular Senescence in Head and Neck Squamous Cell Carcinoma

“…However, numerous HNSCCs are HPV-independent, thus underscoring the need to identify additional genetic alterations in HNSCC. In the September 2016 issue of PLOS Genetics , Majumber et al reported that the Fragile X-related protein 1 (FXR1), an RNA-binding protein, suppresses the senescence response in two different HPV-negative HNSCC cell lines [8]. This further supports the requirement for bypassing senescence in both HPV-positive and -negative HNSCC and sheds light on the putative role of FXR1 in promoting HNSCC.…”

“…In addition to its amplification in lung, breast, and ovarian as well as head and neck cancers [8,9], FXR1 was shown to be down-regulated in other human pathologies such as facioscapulohumeral muscular dystrophy, an inherited myopathy [16]. FXR1 plays an important role in myogenesis in both mouse and Xenopus .…”

“…FXR1 knockout mice die shortly after birth and display disruption of the cellular architecture of skeletal and cardiac muscle [17]. Majumber et al demonstrated that loss of FXR1 not only leads to senescence in cancer cells, but also in normal cells such as mouse embryonic fibroblasts [8]. Considering that cellular senescence limits the muscle stem cell regenerative capacity [18], it is reasonable to envisage that the phenotype observed following FXR1 dysfunction in facioscapulohumeral muscular dystrophy could be caused by concomitant overstimulation of cellular senescence, thus leading to muscle tissue degeneration.…”