RNA-binding protein FXR1 drives cMYC translation by recruiting eIF4F complex to the translation start site

Fragile X-related protein-1 (FXR1) gene is highly amplified in patients with ovarian cancer, and this amplification is associated with increased expression of both FXR1 mRNA and protein. FXR1 expression directly associates with the survival and proliferation of cancer cells. Surface sensing of trans...

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Bibliographic Details
Published in:Cell reports (Cambridge) Vol. 37; no. 5; p. 109934
Main Authors: George, Jasmine, Li, Yongsheng, Kadamberi, Ishaque P., Parashar, Deepak, Tsaih, Shirng-Wern, Gupta, Prachi, Geethadevi, Anjali, Chen, Changliang, Ghosh, Chandrima, Sun, Yunguang, Mittal, Sonam, Ramchandran, Ramani, Rui, Hallgeir, Lopez-Berestein, Gabriel, Rodriguez-Aguayo, Cristian, Leone, Gustavo, Rader, Janet S., Sood, Anil K., Dey, Madhusudan, Pradeep, Sunila, Chaluvally-Raghavan, Pradeep
Format: Journal Article
Language:English
Published: United States Elsevier Inc 02.11.2021
Elsevier
Subjects:
3' Untranslated Regions
Animals
ARE
AU Rich Elements
Cell Line, Tumor
Cell Proliferation
Cell Survival
cMYC
CNV
EIF4F
eIFs
Eukaryotic Initiation Factor-4F - genetics
Eukaryotic Initiation Factor-4F - metabolism
Female
FXR1
Gene Expression Regulation, Neoplastic
Humans
Mice
Mice, Nude
mRNA circularization
ovarian cancer
Ovarian Neoplasms - genetics
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - pathology
Peptide Chain Initiation, Translational
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
RNA Stability
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
Signal Transduction
SUnSET
translation
Tumor Burden
FXR1
ARE
mRNA circularization
ovarian cancer
SUnSET
translation
cMYC
CNV
EIF4F
eIFs
ISSN:2211-1247, 2211-1247
Online Access:Get full text
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Description
Summary:Fragile X-related protein-1 (FXR1) gene is highly amplified in patients with ovarian cancer, and this amplification is associated with increased expression of both FXR1 mRNA and protein. FXR1 expression directly associates with the survival and proliferation of cancer cells. Surface sensing of translation (SUnSET) assay demonstrates that FXR1 enhances the overall translation in cancer cells. Reverse-phase protein array (RPPA) reveals that cMYC is the key target of FXR1. Mechanistically, FXR1 binds to the AU-rich elements (ARE) present within the 3′ untranslated region (3′UTR) of cMYC and stabilizes its expression. In addition, the RGG domain in FXR1 interacts with eIF4A1 and eIF4E proteins. These two interactions of FXR1 result in the circularization of cMYC mRNA and facilitate the recruitment of eukaryotic translation initiation factors to the translation start site. In brief, we uncover a mechanism by which FXR1 promotes cMYC levels in cancer cells. [Display omitted] •CNVs of FXR1 associate with its expression in ovarian cancer•FXR1 promotes the survival and proliferation of ovarian cancer cells•FXR1 binds to AU-rich elements (ARE) within 3′UTR of cMYC•FXR1 promotes the recruitment of eIF4F complex to translation initiation site George et al. demonstrate that FXR1 binds to the AREs within the 3′UTR of MYC mRNA and improves its stability. The authors also show that the RGG domain of FXR1 interacts with eIF4A1 and eIF4E and facilitates recruitment of the eIF4F complex to translation initiation sites for cMYC translation.
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P.C.R. conceived the study, generated hypotheses, and designed the experiments. J.G. designed and performed most of the experiments, including cell cultures, animal experiments, qPCR, microscopy, immunoblots, REMSA, PLA, statistical analyses, preparing figures, and the drafting the manuscript. Y.L. and S.-W.T. performed all the bioinformatics and computational analysis for this study. D.P., A.G., P.G., C.C., or S.M. and I.P.K assisted on animal experiments, animal imaging or in vitro experiments. S.P. and P.C.R. designed the animal experiments. S.P. provided scientific feedback and assisted with manuscript preparation. Y.S. and H.R. assisted on IHC scanning and pathology analysis consultations. G.L.-B., C.R.-A., and A.K.S. incorporated siRNA into nanoliposomes. H.R., J.S.R., R.R., and M.D. edited the manuscript and provided comments. C.G. and M.D. assisted with polysome fractionation and translational experiments. P.C.R. provided scientific direction, established collaborations, prepared the manuscript with J.G., and allocated funding for the work.
AUTHOR CONTRIBUTIONS
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2021.109934