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.
Highlights
The tumor microenvironment plays important roles in cancer, providing a niche for the preferential survival and proliferation of tumor cells
We demonstrate that the production of HA and its related downstream effectors are coordinately controlled post-transcriptionally by the eukaryotic translation initiation factor eIF4E. eIF4E is highly expressed in many cancers and this correlates with increased invasion, metastases and poor prognosis (Assouline et al, 2015; Culjkovic-Kraljacic and Borden, 2013; Gao et al, 2016; Pettersson et al, 2015; Xu et al, 2016)
We found in MM6 cells that eIF4E targeting with ribavirin reduced the mRNA export of the corresponding HA enzymes and CD44 from two- to ninefold depending on the mRNA monitored (Figure 3b)
Summary
The tumor microenvironment plays important roles in cancer, providing a niche for the preferential survival and proliferation of tumor cells. HA is synthesized by hyaluronic acid synthases (HAS), which are single transmembrane proteins localized to the inner-face of the plasma membrane (Kultti et al, 2006; Lenart et al, 2017). Shorter chains are primarily synthesized by HAS3 (Itano et al, 1999; Spicer and McDonald, 1998). These shorter forms of HA are often associated with malignant phenotypes (Slevin et al, 2007; Slevin et al, 2002; West et al, 1985).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
