RNA-binding protein FXR1 drives cMYC translation by mRNA circularization through eIF4F recruitment in ovarian cancer

FXR1 (Fragile X-Related protein 1) gene encodes an RNA binding protein, which is highly amplified or copy-gained in ovarian cancer. We found that amplification and copy-gain of FXR1 increased the expression of FXR1 mRNA and FXR1 protein in ovarian cancer patients and associated with poor prognosis. FXR1 improved cells proliferation and tumor growth, while depletion of FXR1 induced apoptosis and reduced tumor growth both in vitro and in vivo. Through reverse phase protein array (RPPA) we identified that cMYC is the direct target of FXR1 in ovarian cancer cells. Our study demonstrated that FXR1 binds to the AU rich elements (ARE) presents within the 3 untranslated region (UTR) of cMYC. We found that FXR1 binding on UTR leads to the circularization of mRNA through the recruitment of eukaryotic translation initiation factors (eIFs) to the translation start site for cMYC translation. Altogether, our study provides novel evidence on the mechanism how cMYC is regulated by FXR1 CNV in cancer cells for tumor progression.