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FGFR1-Activated Translation of WNT Pathway Components with Structured 5′ UTRs Is Vulnerable to Inhibition of EIF4A-Dependent Translation Initiation

Year: 2018
Type: article
Abstract: Cooperativity between WNT and FGF signaling is well documented in embryonic development and cancer progression, but the molecular mechanisms underlying this cross-talk remain elusive. In this study, we interrogated the dynamics of RNA levels, ribosome occupancy, and protein expression as a function of inducible FGF signaling in mouse mammary glands with constitutive WNT hyperactivation. Multiomics correlation analysis revealed a substantial discrepancy between RNA and ribosome occupancy levels versus protein levels. However, this discrepancy decreased as cells became premalignant and dynamically responded to FGF signaling, implicating the importance of stringent gene regulation in nontransformed cells. Analysis of individual genes demonstrated that acute FGF hyperactivation increased translation of many stem cell self-renewal regulators, including WNT signaling components, and decreased translation of genes regulating cellular senescence. WNT pathway components translationally upregulated by FGF signaling had long and structured 5′ UTRs with a high frequency of polypurine sequences, several of which harbored (CGG)4 motifs that can fold into either stable G-quadruplexes or other stable secondary structures. The FGF-mediated increase in translation of WNT pathway components was compromised by silvestrol, an inhibitor of EIF4A that clamps EIF4A to polypurine sequences to block 43S scanning and inhibits its RNA-unwinding activity important for translation initiation. Moreover, silvestrol treatment significantly delayed FGF-WNT–driven tumorigenesis. Taken together, these results suggest that FGF signaling selectively enhances translation of structured mRNAs, particularly WNT signaling components, and highlight their vulnerability to inhibitors that target the RNA helicase EIF4A. Significance: The RNA helicase EIF4A may serve as a therapeutic target for breast cancers that require FGF and WNT signaling. Cancer Res; 78(15); 4229–40. ©2018 AACR.
DOI: 10.1158/0008-5472.can-18-0631
Authors: Tuan M. Nguyen, Elena B. Kabotyanski, Yongchao Dou, Lucas C. Reineke, Peng Zhang, Xiang H.-F. Zhang, Anna Malovannaya, Sung Yun Jung, Qianxing Mo, Kevin P. Roarty, Yiwen Chen, Bing Zhang, Joel R. Neilson, Richard E. Lloyd, Charles M. Perou, Matthew J. Ellis, Jeffrey M. Rosen
Institutions: Baylor College of Medicine, Chinese Academy of Sciences, Institute of Biophysics, Dan L Duncan Comprehensive Cancer Center, The University of Texas MD Anderson Cancer Center, University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center
Language: English
Open Access status: green
Funders: American Cancer Society, Cancer Prevention and Research Institute of Texas, Virginia and D.K. Ludwig Fund for Cancer Research, Ohio State University, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases
Awards: An integrated approach to dissect the functional network of large non-coding RNA, G2358021521, G2458094374, G2759344090, G2795201161, G2874680091, Recruitment of Rising Stars, Proteomics and Metabolomics Core Facility, Hormonal Regulation of Breast Cancer, Recruitment of First-Time, Tenure-Track Faculty Members, Baylor College of Medicine Comprehensive Cancer Training Program, G9000109225, G9000117358, G9000205897, G9000266605, G9000303739, Baylor College of Medicine Cancer Center - Cancer Center Support Grant, G983901641
OpenAlex ID: W2805240258
FWCI: 1.098
Cites: 49
Cited by: 25
Related to: 10