Background: Molecular mechanisms of the effect of the GOLPH3 oncogenic protein on tumorigenesis remain unclear. Results: GOLPH3 specifically up-regulates sialylation of integrin N-glycans, promotes sialylation-dependent cell migration, and affects AKT signaling. Conclusion: GOLPH3 affects cell biological functions through a specific regulation of sialylation. Significance: The sialylation of N-glycans is important for functions of GOLPH3.

Based on the molecular stent concept, a series of tough double-network hydrogels (St-DN gels) made from the components of proteoglycan aggregates - chondroitin sulfate proteoglycans (1), chondroitin sulfate (2), and sodium hyaluronate (3) - are successfully developed in combination with a neutral biocompatible polymer. This work demonstrates a promising method to create biopolymer-based tough hydrogels for biomedical applications.

Background: Molecular mechanisms underlying the effect of sialylation on tumor progression remain unclear. Results: ST6GAL1 promoted the TGF-␤-induced EMT through down-regulation of E-cadherin-mediated cell adhesion and up-regulation of integrin-mediated cell migration. Conclusion: Expression of ST6GAL1 is critical for sufficient induction of EMT. Significance: ␣2,6-Sialylation of N-glycans may play a role in EMT.

Up-regulation of core fucosylation catalyzed by a1,6-fucosyltransferase (Fut8) has been observed in hepatocellular carcinoma (HCC). Here, to explore the role of Fut8 expression in hepatocarcinogensis, we established the chemical-induced HCC models in the male wildtype (WT; Fut8 +/+ ), hetero (Fut8 +/2 ), and knockout (KO; Fut8 2/2 ) mice by use of diethylnitrosamine (DEN) and pentobarbital (PB). In the Fut8 +/+ and Fut8 +/2 mice, multiple large and vascularized nodules were induced with an increased expression of Fut8 after DEN and PB treatment. However, the formation of HCC in Fut8 2/2 mice was suppressed almost completely. This potent inhibitory effect of Fut8 deficiency on tumorigenesis was also confirmed by the abolished tumor formation of Fut8 KO human hepatoma cell line cells by use of a xenograft tumor model. Furthermore, loss of the Fut8 gene resulted in attenuated responses to epidermal growth factor (EGF) and hepatocyte growth factor (HGF) in the HepG2 cell line, which provides the possible mechanisms for the contribution of Fut8 to hepatocarcinogensis. Taken together, our study clearly demonstrated that core fucosylation acts as a critical functional modulator in the liver and implicated Fut8 as a prognostic marker, as well as a novel, therapeutic target for HCC.-Wang, Y., Fukuda, T., Isaji, T., Lu, J., Im, S., Hang, Q., Gu, W., Hou, S., Ohtsubo, K., Gu, J. Loss of a1,6-fucosyltransferase inhibits chemical induced hepatocellular carcinoma and tumorigenesis by down-regulating several cell signaling pathways. FASEB J. 29, 3217-3227 (2015). www.fasebj.org

Altered glycosylation is a common feature of cancer cells. It takes a variety of forms, which includes loss of expression or excessive expression of some structures, the accumulation of precursors, the appearance of novel structures, etc. Notably, these changes in glycan structure do not occur as a random consequence of disorder biology. Only a limited subset of oligosaccharides is found frequently enriched on the tumor cell surface and implicated in different tumor phenotypes. Among these, altered sialylation has long been associated with metastatic cell behaviors such as invasion and enhanced cell survival and accumulating evidence points to the alteration occurring in the sialic acid linkage to other sugars, which normally exists in three main configurations: α2,3, α2,6, and α2,8, catalyzed by a group of sialyltransferases. The aberrant expression of all three configurations has been described in cancer progression. However, the increased α2,6 sialylation catalyzed by β-galactoside α2,6 sialyltranferase 1 (ST6Gal I) is frequently observed in many types of the cancers. In this review, we describe the findings on the role of ST6Gal I in cancer progression, and highlight in particular the knowledge of how ST6Gal I-mediated α2,6 sialylated glycans or sialylated carrier proteins regulate cell signaling to promote the malignant phenotype of human carcinoma.

Mucin-type -glycosylation is the most abundant type of-glycosylation. It is initiated by the members of the polypeptide -acetyl-α-galactosaminyltransferase (ppGalNAc-T) family and closely associated with both physiological and pathological conditions, such as coronary artery disease or Alzheimer's disease. The lack of direct and selective inhibitors of ppGalNAc-Ts has largely impeded research progress in understanding the molecular events in mucin-type-glycosylation. Here, we report that a small molecule, the plant flavonoid luteolin, selectively inhibits ppGalNAc-Ts and in cells. We found that luteolin inhibits ppGalNAc-T2 in a peptide/protein-competitive manner but not promiscuously ( via aggregation-based activity). X-ray structural analysis revealed that luteolin binds to the PP motif-binding site found in most protein substrates, which was further validated by comparing the interactions of luteolin with wild-type enzyme and with mutants using H NMR-based binding experiments. Functional studies disclosed that luteolin at least partially reduced production of β-amyloid protein by selectively inhibiting the activity of ppGalNAc-T isoforms. In conclusion, our study provides key structural and functional details on luteolin inhibiting ppGalNAc-T activity, opening up the way for further optimization of more potent and specific ppGalNAc-T inhibitors. Moreover, our findings may inform future investigations into site-specific-GalNAc glycosylation and into the molecular mechanism of luteolin-mediated ppGalNAc-T inhibition.

N-Glycosylation of integrin α5β1 plays important roles in cell biologic functions; however, the mechanisms that underlie those roles remain poorly understood. Here, we present evidence that the membrane-proximal N-glycosylation on integrin β1 could positively regulate cell migration by promoting β1 activation. The S4-6 β1 mutant contains only 3 N-glycosylation sites, which are essential for α5 and β1 heterodimer formation, and despite only a small difference in expression levels of α5β1 between wild-type and S4-6 mutant, cell spreading and migration of the S4-6 mutant was significantly decreased compared with that of control. Consistent with these phenotypes, β1-mediated cellular signaling and its activation were clearly suppressed in the S4-6 mutant. Of note, these developments could be rescued by restoration of N-glycosylation sites in the membrane-proximal domain. Further study on the regulatory mechanisms suggested that membrane-proximal N-glycosylation is critical for intermolecular interactions between integrin β1 and other cell membrane proteins, such as syndecan-4 and epidermal growth factor receptor. Moreover, α2,6-sialylation is required for β1 activation. These data suggest a novel regulatory mechanism wherein N-glycosylation near the cell membrane on β1 may serve as a platform that facilitates its complex formation on the cell membrane, thereby affecting integrin-mediated functions.-Hou, S., Hang, Q., Isaji, T., Lu, J., Fukuda, T., Gu, J. Importance of membrane-proximal N-glycosylation on integrin β1 in its activation and complex formation.

Core fucosylation is an important post-translational modification, which is catalyzed by α1,6-fucosyltransferase (Fut8). Increased expression of Fut8 has been shown in diverse carcinomas including hepatocarcinoma. In this study, we investigated the role of Fut8 expression in liver regeneration by using the 70% partial hepatectomy (PH) model, and found that Fut8 is also critical for the regeneration of liver. Interestingly, we show that the Fut8 activities were significantly increased in the beginning of PH (~4d), but returned to the basal level in the late stage of PH. Lacking Fut8 led to delayed liver recovery in mice. This retardation mainly resulted from suppressed hepatocyte proliferation, as supported not only by a decreased phosphorylation level of epidermal growth factor (EGF) receptor and hepatocyte growth factor (HGF) receptor in the liver of Fut8−/− mice in vivo, but by the reduced response to exogenous EGF and HGF of the primary hepatocytes isolated from the Fut8−/− mice. Furthermore, an administration of L-fucose, which can increase GDP-fucose synthesis through a salvage pathway, significantly rescued the delayed liver regeneration of Fut8+/− mice. Overall, our study provides the first direct evidence for the involvement of Fut8 in liver regeneration.