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| Content Provider | Springer Nature Link |
|---|---|
| Author | Deen, Ashik Jawahar Arasu, Uma Thanigai Pasonen Seppänen, Sanna Hassinen, Antti Takabe, Piia Wojciechowski, Sara Kärnä, Riikka Rilla, Kirsi Kellokumpu, Sakari Tammi, Raija Tammi, Markku Oikari, Sanna |
| Copyright Year | 2016 |
| Abstract | Hyaluronan content is a powerful prognostic factor in many cancer types, but the molecular basis of its synthesis in cancer still remains unclear. Hyaluronan synthesis requires the transport of hyaluronan synthases (HAS1-3) from Golgi to plasma membrane (PM), where the enzymes are activated. For the very first time, the present study demonstrated a rapid recycling of HAS3 between PM and endosomes, controlled by the cytosolic levels of the HAS substrates UDP-GlcUA and UDP-GlcNAc. Depletion of UDP-GlcNAc or UDP-GlcUA shifted the balance towards HAS3 endocytosis, and inhibition of hyaluronan synthesis. In contrast, UDP-GlcNAc surplus suppressed endocytosis and lysosomal decay of HAS3, favoring its retention in PM, stimulating hyaluronan synthesis, and HAS3 shedding in extracellular vesicles. The concentration of UDP-GlcNAc also controlled the level of O-GlcNAc modification of HAS3. Increasing O-GlcNAcylation reproduced the effects of UDP-GlcNAc surplus on HAS3 trafficking, while its suppression showed the opposite effects, indicating that O-GlcNAc signaling is associated to UDP-GlcNAc supply. Importantly, a similar correlation existed between the expression of GFAT1 (the rate limiting enzyme in UDP-GlcNAc synthesis) and hyaluronan content in early and deep human melanomas, suggesting the association of UDP-sugar metabolism in initiation of melanomagenesis. In general, changes in glucose metabolism, realized through UDP-sugar contents and O-GlcNAc signaling, are important in HAS3 trafficking, hyaluronan synthesis, and correlates with melanoma progression. |
| Starting Page | 3183 |
| Ending Page | 3204 |
| Page Count | 22 |
| File Format | |
| ISSN | 1420682X |
| Journal | Cellular and Molecular Life Sciences |
| Volume Number | 73 |
| Issue Number | 16 |
| e-ISSN | 14209071 |
| Language | English |
| Publisher | Springer International Publishing |
| Publisher Date | 2016-02-16 |
| Publisher Place | Cham |
| Access Restriction | Subscribed |
| Subject Keyword | 4MU Mannose Glucosamine GNPDA UGDH OGT Cell Biology Biomedicine general Life Sciences Biochemistry |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Molecular Biology Molecular Medicine Pharmacology Cellular and Molecular Neuroscience |
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