PomGnT1 enhances temozolomide resistance by activating epithelial-mesenchymal transition signaling in glioblastoma

Liu, Qi; Xue, Yingwei; Chen, Qingshan; Chen, Huairui; Zhang, Xiaofei; Wang, Leiping; Han, Cong; Que, Shuanglin; Lou, Meiqing; Jin, Lan

doi:10.3892/or.2017.5964

Cited by 11 publications

(11 citation statements)

References 32 publications

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“…Aberrant molecular changes, including MGMT overexpression induced by MGMT promoter unmethylation, have been shown to induce resistance to TMZ treatment by DNA damage repair (21,22). In addition, previous studies found a close link between EMT, the Wnt signal pathway, and the TMZ resistance phenotype in gliomas (13,(23)(24)(25). These results were confirmed by Ho et al (26) and our study.…”

Section: Discussionsupporting

confidence: 91%

Identifying Predictive Gene Expression and Signature Related to Temozolomide Sensitivity of Glioblastomas

et al. 2020

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Section: Discussionsupporting

confidence: 91%

Identifying Predictive Gene Expression and Signature Related to Temozolomide Sensitivity of Glioblastomas

et al. 2020

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“…Our results on POMGNT1-deficient HEK293T and fibroblast cells point to a partial EMT event that is accompanied by reduced expression of epithelial and increased expression for most of the mesenchymal markers tested. Very recently differential expression of POMGNT1 in human glioma cell lines has been reported to impact on the expression of some EMT marker proteins(17) further corroborating the general relevance and validity of our HEK293T cell model. We also observe a predominant induction of MMPs that is indicative of an EMT-like transition.…”

supporting

confidence: 83%

“…However, also clusters of granule cells which failed to migrate have been frequently observed (15). In addition to its important role during mammalian development, POMGNT1 has recently been linked to the progression of glioblastoma, fatal primary brain tumors with survival time of 12-15 months, as well as the resistance of glioblastoma cells to the chemotherapeutic agent temozolomide (16,17). Strikingly, in glioblastoma models increased cell-cell adhesion has been observed when POMGNT1 is missing (16).…”

Section: Introductionmentioning

confidence: 99%

Glycosyltransferase POMGNT1 deficiency affects N-cadherin-mediated cell-cell adhesion

Noor

Hoffmann

Rinis

et al. 2020

Preprint

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Defects in protein O-mannosylation lead to severe congenital muscular dystrophies known as α-dystroglycanopathy. A hallmark of these diseases is the loss of the O-mannose-bound matriglycan on α-dystroglycan, which leads to a reduction in cell adhesion to the extracellular matrix. Mutations in protein O-mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGNT1), which is crucial for the elongation of O-mannosyl glycans, are mainly associated with muscle-eye-brain (MEB) disease. In addition to defects in cell-extracellular matrix adhesion, aberrant cell-cell adhesion has occasionally been observed in response to defects in POMGNT1. However, direct molecular mechanisms are largely unknown. We used POMGNT1 knock-out HEK293T cells and fibroblasts from a MEB patient to gain a deeper insight into the molecular changes in POMGNT1 deficiency. A combination of biochemical and molecular biological techniques with proteomics, glycoproteomics and glycomics revealed that a lack of POMGNT1 activity strengthens cell-cell adhesion. We demonstrate that the altered intrinsic adhesion properties are due to an increased abundance of N-cadherin (N-Cdh). In addition, site-specific changes in the N-glycan structures in the extracellular domain of N-Cdh were detected, which positively impact on homotypic interactions. We found that in POMGNT1 deficient cells ERK1/2 and p38 signaling pathways are activated and transcriptional changes that are comparable to the epithelial-mesenchymal transition (EMT) are triggered, defining a possible molecular mechanism underlying the observed phenotype. Our study indicates that changes in cadherin-mediated cell-cell adhesion and other EMT-related processes may contribute to the complex clinical symptoms of MEB or α-dystroglycanopathy in general, and suggests a previously underestimated impact of changes in O-mannosylation on N-glycosylation.

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“…Here we report its up-regulation in lymphoid neoplasm diffuse large B-cell lymphoma and in skin cutaneous melanoma (Table 1), which is associated to an unfavorable prognosis in both cancers (Figure 1). Interestingly, POMGNT1 is reported to be up-regulated in glioblastoma apoptosis resistant cell lines, whereas the POMGNT1 knock-down enhanced apoptosis when cells are treated with temozolomide [123]. The STRING analysis here performed reveals that POMGNT1 interacts with DAG1 (Figure 2).…”

Section: Candidate Markers and Associated Functional Partnersmentioning

confidence: 76%

Computational Approaches for Cancer-Fighting: From Gene Expression to Functional Foods

Monticolo

Chiusano

2021

Cancers

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It is today widely accepted that a healthy diet is very useful to prevent the risk for cancer or its deleterious effects. Nutrigenomics studies are therefore taking place with the aim to test the effects of nutrients at molecular level and contribute to the search for anti-cancer treatments. These efforts are expanding the precious source of information necessary for the selection of natural compounds useful for the design of novel drugs or functional foods. Here we present a computational study to select new candidate compounds that could play a role in cancer prevention and care. Starting from a dataset of genes that are co-expressed in programmed cell death experiments, we investigated on nutrigenomics treatments inducing apoptosis, and searched for compounds that determine the same expression pattern. Subsequently, we selected cancer types where the genes showed an opposite expression pattern and we confirmed that the apoptotic/nutrigenomics expression trend had a significant positive survival in cancer-affected patients. Furthermore, we considered the functional interactors of the genes as defined by public protein-protein interaction data, and inferred on their involvement in cancers and/or in programmed cell death. We identified 7 genes and, from available nutrigenomics experiments, 6 compounds effective on their expression. These 6 compounds were exploited to identify, by ligand-based virtual screening, additional molecules with similar structure. We checked for ADME criteria and selected 23 natural compounds representing suitable candidates for further testing their efficacy in apoptosis induction. Due to their presence in natural resources, novel drugs and/or the design of functional foods are conceivable from the presented results.

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PomGnT1 enhances temozolomide resistance by activating epithelial-mesenchymal transition signaling in glioblastoma

Cited by 11 publications

References 32 publications

Identifying Predictive Gene Expression and Signature Related to Temozolomide Sensitivity of Glioblastomas

Identifying Predictive Gene Expression and Signature Related to Temozolomide Sensitivity of Glioblastomas

Glycosyltransferase POMGNT1 deficiency affects N-cadherin-mediated cell-cell adhesion

Computational Approaches for Cancer-Fighting: From Gene Expression to Functional Foods

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