RNA Binding Protein FXR1‐miR301a‐3p axis contributes to p21WAF1 degradation in oral cancer

Abstract

RNA‐binding proteins (RBPs) associate with primary, precursor, and mature microRNAs (miRNAs), which in turn control mature miRNA levels, and post‐transcriptional gene regulation (PTR). However, the mechanistic basis of miRNA interaction and stability by RBP remains largely elusive. To understand how RBPs contribute to miRNA stability and PTR, we analyzed miRNAs that are controlled and stabilized by RBP Fragile X Mental Retardation protein‐ 1 (FXR1) in head and neck squamous cell carcinoma (HNSCC). We find that FXR1controls the expression of a subset of mature miRNAs, including a highly expressed oncogenic miR301a‐3p in HNSCC cells. We also observed that FXR1 controls the stability of miR301a‐3p by blocking 3′ to 5′ exoribonuclease activity of Polyribonucleotide Nucleotidyltransferase 1 (PNPT1). The miR301a‐3p is degraded by PNPT1 in the absence of FXR1 in oral cancer cells, and the degradation is rescued in co‐knockdown of FXR1 and PNPT1. Also, our in vitro findings show that FXR1 bound miRNA complex protects miR301a‐3p from PNPT1‐mediated miRNA degradation. This work also reveals that FXR1 knockdown destabilizes miR301a‐3p that degrades p21 mRNA, which leads to an increase in p21 accumulation, which explaining why overexpressed FXR1 and miR301a‐3p in HNSCC display p21 downregulation. Thus, our work illustrates the unique role of FXR1 that is critical for the stability of a subset of mature miRNAs or at least miR301a‐3p to target p21, thereby promoting the growth and proliferation of HNSCC.Support or Funding InformationDE025920 and P30 CA138313