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.