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

George, J.; Li, Y.; Parashar, D.; Tsaih, S.-W.; Gupta, P.; Geethadevi, A.; Kadembari, I.; Ghosh, C.; Sun, Y.; Ramchandran, R.; Rader, J. S.; Rui, H.; Dey, M.; Pradeep, S.; Chaluvally-Raghavan, P.

doi:10.1101/2020.07.19.210252

bioRxiv · 10.1101/2020.07.19.210252

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

George, J.·Li, Y.·Parashar, D.·Tsaih, S.-W.·Gupta, P.·Geethadevi, A.·Kadembari, I.·Ghosh, C.·Sun, Y.·Ramchandran, R.·Rader, J. S.·Rui, H.·Dey, M.·Pradeep, S.·Chaluvally-Raghavan, P.

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Abstract

BackgroundThe RNA-binding protein FXR1 (fragile X-related protein 1) has been implicated as an important regulator of post-transcriptional changes of mRNAs. However, its role in mRNA circularization and recruitment of eukaryotic translation initiation factors for protein translation remains obscure. Here, we aimed to investigate the molecular mechanisms and potential clinical applications of FXR1 in ovarian cancer growth and progression. MethodsFXR1 copy number variation, mRNA expression, protein levels, and their association with prognosis were determined in clinical datasets. An orthotopic ovarian cancer model and bioluminescence imaging were used for preclinical evaluation of FXR1 in vivo. Reverse phase protein arrays (RPPA) and qPCR arrays were performed to identify FXR1s key targets and downstream effects. SUnSET and polysome profiling were used to determine the translational effects of FXR1. Immunoprecipitation and immunofluorescence were performed to identify the interaction between FXR1 and cMYC mRNA and eIF4F complex. RNA-immunoprecipitation (RIP), RNA electrophoretic mobility shift assays (REMSA), proximity ligation assays (PLA), and biochemical assays were used to identify the specific site on cMYC mRNA to which FXR1 binds to promote mRNA circularization and translation. ResultsWe found that amplification and copy-gain of FXR1 increased the expression of FXR1 mRNA and FXR1 protein in ovarian cancer patients, and these events associated with poor prognosis. We demonstrated that FXR1 binds to AU-rich elements (ARE) within the 3 untranslated region (3UTR) of cMYC. As a consequence, FXR1 binding to cMYC 3UTR leads to the circularization of mRNA and facilitated the recruitment of eukaryotic translation initiation factors (eIFs) to translation start site for improving protein synthesis. ConclusionWe found that FXR1 upregulates a known oncogene, cMYC, by binding to AU-rich elements within the 3UTR, leading to the recruitment of the eIF4F complex for cMYC translation. Our findings uncover a novel mechanism of action of FXR1 in tumorigenesis and provides opportunities to use FXR1 and its downstream effectors as biomarkers or therapeutic targets in ovarian and other cancers.

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George, J., Li, Y., Parashar, D., Tsaih, S.-W., Gupta, P., Geethadevi, A., Kadembari, I., Ghosh, C., Sun, Y., Ramchandran, R., Rader, J. S., Rui, H., Dey, M., Pradeep, S., Chaluvally-Raghavan, P.. 2020-07-19. RNA-binding protein FXR1 drives cMYC translation by mRNA circularization through eIF4F recruitment in ovarian cancer. https://doi.org/10.1101/2020.07.19.210252

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