The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity

Abstract

The microenvironment provides a functional substratum supporting tumour growth. Hyaluronan (HA) is a major component of this structure. While the role of HA in malignancy is well-defined, the mechanisms driving its biosynthesis in cancer are poorly understood. We show that the eukaryotic translation initiation factor eIF4E, an oncoprotein, drives HA biosynthesis. eIF4E stimulates production of enzymes that synthesize the building blocks of HA, UDP-Glucuronic acid and UDP-N-Acetyl-Glucosamine, as well as hyaluronic acid synthase which forms the disaccharide chain. Strikingly, eIF4E inhibition alone repressed HA levels as effectively as directly targeting HA with hyaluronidase. Unusually, HA was retained on the surface of high-eIF4E cells, rather than being extruded into the extracellular space. Surface-associated HA was required for eIF4E’s oncogenic activities suggesting that eIF4E potentiates an oncogenic HA program. These studies provide unique insights into the mechanisms driving HA production and demonstrate that an oncoprotein can co-opt HA biosynthesis to drive malignancy.

The eukaryotic translation initiation factor eIF4E elevates steady-state m 7 G capping of coding and noncoding transcripts

“…In the nucleus, eIF4E binds ∼3,000 capped mRNAs which typically are its export targets (36). By contrast, in the cytoplasm, eIF4E binds the majority of capped mRNAs regardless of whether eIF4E enhances their translation efficiency (28,32,(36)(37)(38). Thus, the identification of eIF4E-bound transcripts from the nucleus provides a straightforward strategy for the discovery of target RNAs.…”

“…Many of the other noncoding RNAs identified are competing endogenous RNAs which act as sponges for tumor suppressive microRNAs. In parallel, many of the coding transcripts identified are similarly implicated in cancer, such as Mdm2, Myc, Mcl1, and CTNNB1 (29,32,33,37,56). Some of these RNAs play roles in the same biochemical pathways, such as CTNNB1 and the lncRNA that protects it [SLC4O1-AS1 (57)].…”

The Impact of Post-transcriptional Control: Better Living Through RNA Regulons

“…For instance, RIP-Seq analysis in lymphoma cells indicated that nuclear eIF4E binds over 3000 mRNAs that encode proteins acting in lymphoma-sustaining pathways such as B-cell receptor signaling (Bcl2, Bcl6) and DNA methylation/epigenetic regulation (DNMT1, DNMT3A, HDAC1) ( Culjkovic-Kraljacic et al, 2016 ). In AML and osteosarcoma cells, eIF4E coordinately increases the export of transcripts encoding all the proteins involved in hyaluronan synthesis ( Zahreddine et al, 2017 ). Hyaluronan is a large polysaccharide with traditional roles in building the extracellular matrix, and more recently was found to encapsulate some tumor cells ( Setala et al, 1999 ; Auvinen et al, 2000 ; Kemppainen et al, 2005 ).…”

“…Hyaluronan is a large polysaccharide with traditional roles in building the extracellular matrix, and more recently was found to encapsulate some tumor cells ( Setala et al, 1999 ; Auvinen et al, 2000 ; Kemppainen et al, 2005 ). Indeed, Hyaluronan (HA) production was found to be required for the metastatic and invasive properties associated with eIF4E, and thus serves as the first case where this HA coat was shown to contribute to the oncogenic phenotype ( Zahreddine et al, 2017 ). Indeed, inhibition of this regulon with RNAi to eIF4E or treatment with the cap competitor ribavirin impaired the export of the RNAs encoding the HA machinery, reduced HA production and decreased the invasive and metastatic activities of these cells.…”

“…Indeed, inhibition of this regulon with RNAi to eIF4E or treatment with the cap competitor ribavirin impaired the export of the RNAs encoding the HA machinery, reduced HA production and decreased the invasive and metastatic activities of these cells. Indeed, eIF4E overexpression in the presence of RNAi knockdown to Has3 (hyaluronan synthase 3) mRNA, similarly reduced invasion and metastatic potential indicating that the HA pathway is critical for these eIF4E-driven activities ( Zahreddine et al, 2017 ).…”