N-glycosylated SGK196 suppresses the metastasis of basal-like breast cancer cells

Xu, Cheng; Zhang, Meichao; Bian, Lei; Li, Yanyan; Yuan, Yao; Li, Dong

doi:10.1038/s41389-019-0188-1

Cited by 10 publications

(10 citation statements)

References 44 publications

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“…Altered glycosylation, in turn, may lead to improper localization and disrupt GCNT2 enzyme function by blocking access to substrates. In fact, N ‐glycosylation modifications have been demonstrated to be crucial regulators of function in other glycoproteins involved in cancer pathogenesis, including CD147 and the O‐mannose kinase SGK196 73,74 . Therefore, altering the glycosylation at Asn41 may be another opportunity for cells to execute GCNT2 regulation and influence cancer progression, although it is not yet known whether the absence of this glycosylation has significant functional consequences.…”

Section: Mechanisms Of Gcnt2 Expression Controlmentioning

confidence: 99%

Melanoma‐associated glycosyltransferase GCNT2 as an emerging biomarker and therapeutic target*

et al. 2021

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Summary In metastatic melanoma, with a dismal survival rate and propensity for treatment resistance and recurrence, it is critical to establish biomarkers that better predict treatment response and disease severity. The melanoma glycome, composed of complex carbohydrates termed glycans, is an under‐investigated area of research, although it is gaining momentum in the cancer biomarker and therapeutics field. Novel findings suggest that glycans play a major role in influencing melanoma progression and could be exploited for prognosticating metastatic activity and/or as therapeutic targets. In this review, we discuss the role of aberrant glycosylation, particularly the specialized function of β1,6 N‐acetylglucosaminyltransferase 2 (GCNT2), in melanoma pathogenesis and summarize mechanisms of GCNT2 regulation to illuminate its potential as a predictive marker and therapeutic target.

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Section: Mechanisms Of Gcnt2 Expression Controlmentioning

confidence: 99%

Melanoma‐associated glycosyltransferase GCNT2 as an emerging biomarker and therapeutic target*

et al. 2021

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“…Accumulating evidences have indicated that aberrant N-glycosylation occurs frequently in tumors and is closely associated with cancer metastasis ( 37 – 39 ). Our previous studies indicated that TIM-4 overexpression significantly promoted EMT process of NSCLC cells ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

N-Glycosylation at Asn291 Stabilizes TIM-4 and Promotes the Metastasis of NSCLC

Chen

Wang

et al. 2022

Front. Oncol.

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T-cell immunoglobulin domain and mucin domain 4 (TIM-4) is a transmembrane protein that promotes epithelial-mesenchymal transition (EMT), migration and invasion of non-small cell lung cancer (NSCLC) cells. Most transmembrane proteins are modified by N-glycosylation and the importance of protein N-glycosylation in cancer cell metastasis has been well appreciated. However, whether TIM-4 is modified by N-glycosylation and the role of TIM-4 N-glycosylation in NSCLC remains largely unknown. In the current study, we reported that TIM-4 was extensively N-glycosylated at Asn291. After the removal of N-glycosylation, the stability of TIM-4 protein was decreased and TIM-4 was more susceptible to degradation by ER-localized ubiquitin ligase-mediated ERAD. Thus, the expression of TIM-4 on the cell surface was decreased, which suppressed TIM-4-mediated metastasis in NSCLC. In summary, the present study identifies TIM-4 N-glycosylation and its role in NSCLS migration, which would provide a valuable biomarker for developing drugs targeting N-glycosylation at Asn291 on TIM-4.

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“…As a further example, glycosylated wildtype SKG196 can inhibit cancer cell growth; however, upon deglycosylation, it can promote cancer via the PI3K/AKT/ GSK3β signaling pathway. 86 Additionally, an ATPase that normally activates cancer cell growth suppresses cancer cell growth upon the deglycosylation of E-cadherin. 87,88 Moreover, the glycosylation site modified in the cancer state has been found to play a synergistic role in cancer development.…”

Section: ■ Discussionmentioning

confidence: 99%

“…In the early stages of this work, we hypothesized that N79 glycan was involved in CES1 secretion as we previously observed much higher (>9-fold) plasma CES1 concentrations in patients with HCC than in healthy donors.10; however, it turned out to be an important determinant of cell growth rather than to its extracellular secretion (Figure ). As a further example, glycosylated wild-type SKG196 can inhibit cancer cell growth; however, upon deglycosylation, it can promote cancer via the PI3K/AKT/GSK3β signaling pathway . Additionally, an ATPase that normally activates cancer cell growth suppresses cancer cell growth upon the deglycosylation of E-cadherin. , Moreover, the glycosylation site modified in the cancer state has been found to play a synergistic role in cancer development …”

Section: Discussionmentioning

confidence: 99%

Potential Regulatory Role of Human-Carboxylesterase-1 Glycosylation in Liver Cancer Cell Growth

Kim

et al. 2020

J. Proteome Res.

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We previously reported that human carboxylesterase 1 (CES1), a serine esterase containing a unique N-linked glycosyl group at Asn79 (N79 CES1), is a candidate serological marker of hepatocellular carcinoma (HCC). CES1 is normally present at low-to-undetectable levels in normal human plasma, HCC tumors, and major liver cancer cell lines. To investigate the potential mechanism underlying the suppression of CES1 expression in liver cancer cells, we took advantage of the low detectability of this marker in tumors by overexpressing CES1 in multiple HCC cell lines, including stable Hep3B cells. We found that the population of CES1-overexpressing (OE) cells decreased and that their doubling time was longer compared with mock control liver cancer cells. Using interactive transcriptome, proteome, and subsequent Gene Ontology enrichment analysis of CES1-OE cells, we found substantial decreases in the expression levels of genes involved in cell cycle regulation and proliferation. This antiproliferative function of the N79 glycan of CES1 was further supported by quantitative real-time polymerase chain reaction, flow cytometry, and an apoptosis protein array assay. An analysis of the levels of key signaling target proteins via Western blotting suggested that CES1 overexpression exerted an antiproliferative effect via the PKD1/PKCμ signaling pathway. Similar results were also seen in another HCC cell line (PLC/RFP/5) after transient transfection with CES1 but not in similarly treated non-HCC cell lines (e.g., HeLa and Tera-1 cells), suggesting that CES1 likely exerts a liver cell-type-specific suppressive effect. Given that the N-linked glycosyl group at Asn79 (N79 glycan) of CES1 is known to influence CES1 enzyme activity, we hypothesized that the post-translational modification of CES1 at N79 may be linked to its antiproliferative activity. To investigate the regulatory effect of the N79 glycan on cellular growth, we mutated the single N-glycosylation site in CES1 from Asn to Gln (CES1-N79Q) via site-directed mutagenesis. Fluorescence 2-D difference gel electrophoresis protein expression analysis of cell lysates revealed an increase in cell growth and a decrease in doubling time in cells carrying the N79Q mutation. Thus our results suggest that CES1 exerts an antiproliferative effect in liver cancer cells and that the single N-linked glycosylation at Asn79 plays a potential regulatory role. These functions may underlie the undetectability of CES1 in human HCC tumors and liver cancer cell lines. Mass spectrometry data are available via ProteomeXchange under the identifier PXD021573.

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N-glycosylated SGK196 suppresses the metastasis of basal-like breast cancer cells

Cited by 10 publications

References 44 publications

Melanoma‐associated glycosyltransferase GCNT2 as an emerging biomarker and therapeutic target*

Melanoma‐associated glycosyltransferase GCNT2 as an emerging biomarker and therapeutic target*

N-Glycosylation at Asn291 Stabilizes TIM-4 and Promotes the Metastasis of NSCLC

Potential Regulatory Role of Human-Carboxylesterase-1 Glycosylation in Liver Cancer Cell Growth

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