UDP-sugar substrates of HAS3 regulate its O-GlcNAcylation, intracellular traffic, extracellular shedding and correlate with melanoma progression

被引:43
作者
Deen, Ashik Jawahar [1 ]
Arasu, Uma Thanigai [1 ]
Pasonen-Seppanen, Sanna [1 ]
Hassinen, Antti [4 ]
Takabe, Piia [1 ]
Wojciechowski, Sara [3 ]
Karna, Riikka [1 ]
Rilla, Kirsi [1 ]
Kellokumpu, Sakari [4 ]
Tammi, Raija [1 ]
Tammi, Markku [1 ]
Oikari, Sanna [1 ,2 ]
机构
[1] Univ Eastern Finland, Inst Biomed, Sch Med, Kuopio 70210, Finland
[2] Univ Eastern Finland, Inst Dent, Sch Med, Kuopio 70210, Finland
[3] Univ Eastern Finland, AI Virtanen Inst Mol Sci, Sch Med, Kuopio 70210, Finland
[4] Univ Oulu, Fac Biochem & Mol Med, Oulu 90014, Finland
关键词
4MU; Mannose; Glucosamine; GNPDA; UGDH; OGT; HYALURONAN SYNTHASE 2; N-ACETYLGLUCOSAMINE; DOWN-REGULATION; E-CADHERIN; CANCER; ACCUMULATION; METABOLISM; CD44; PHOSPHORYLATION; TRANSCRIPTION;
D O I
10.1007/s00018-016-2158-5
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:3183 / 3204
页数:22
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