High LARGE1 Expression May Predict Benefit from Adjuvant Chemotherapy in Resected Non-Small-Cell Lung Cancer

Liu, Yü; Huang, Shirui; Kuang, Mengjiao; Wang, Huiyan; Xie, Qipeng

doi:10.2147/pgpm.s271516

Cited by 4 publications

(4 citation statements)

References 62 publications

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“…Five DEGTs were randomly selected and were found to be reported as biomarkers ranging from prognostic biomarkers to risk assessment biomarkers. LARGE1 is a prognostic biomarker in epithelium derived cancers (Liu et al 2021). PYGB , indicated as a potential high-value GT in several experiments described herein is a prognostic biomarker in ovarian cancer (Zhou et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Differential expression of glycosyltransferases identified through comprehensive pan-cancer analysis

Vora

Cauley

et al. 2021

Preprint

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Despite accumulating evidence supporting a role for glycosylation in cancer progression and prognosis, the complexity of the human glycome and glycoproteome poses many challenges to understanding glycosylation-related events in cancer. In this study, a multifaceted genomics approach was applied to analyze the impact of differential expression of glycosyltransferases (GTs) in 16 cancers. An enzyme list was compiled and curated from numerous resources to create a consensus set of GTs. Resulting enzymes were analyzed for differential expression in cancer, and findings were integrated with experimental evidence from other analyses, including: similarity of healthy expression patterns across orthologous genes, miRNA expression, automatically-mined literature, curation of known cancer biomarkers, N-glycosylation impact, and survival analysis. The resulting list of GTs comprises 222 human enzymes based on annotations from five databases, 84 of which were differentially expressed in more than five cancers, and 14 of which were observed with the same direction of expression change across all implicated cancers. 25 high-value GT candidates were identified by cross-referencing multimodal analysis results, including PYGM, FUT6 and additional fucosyltransferases, several UDP-glucuronosyltransferases, and others, and are suggested for prioritization in future cancer biomarker studies. Relevant findings are available through OncoMX at https://data.oncomx.org, and the overarching pipeline can be used as a framework for similarly analysis across diverse evidence types in cancer. This work is expected to improve the understanding of glycosylation in cancer by transparently defining the space of glycosyltransferase enzymes and harmonizing variable experimental data to enable improved generation of data-driven cancer biomarker hypotheses.

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Section: Discussionmentioning

confidence: 99%

Differential expression of glycosyltransferases identified through comprehensive pan-cancer analysis

Vora

Cauley

et al. 2021

Preprint

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“…Separately, LARGE1 mRNA expression data, retrieved from the Oncomine database, have been compared between cancerous and healthy tissues of different types. A deficient expression of LARGE1 was detected in colon adenocarcinoma (by -1.30-fold), prostate cancer (by -1.61-fold), infiltrating urinary-bladder cancer (by -1.85-fold), breast carcinoma (by -1.20-fold), glioma (by -2.63-fold) and melanoma (by -1.45-fold) [106], as well as in renal cell carcinoma (clear cells) (by -1.72 or -1.45fold) [76,106], rhabdomyosarcoma [96] and non-smallcell lung cancer [125]. Interestingly, the LARGE1 gene was originally identified at a chromosomal region frequently deleted in human meningiomas [132] that, since it falls within a common fragile site, it is prone to suffer breaks and deletions in other cancer types [133].…”

Section: Alterations In the Expression Of Dystroglycanopathy-associat...mentioning

confidence: 99%

Involvement of abnormal dystroglycan expression and matriglycan levels in cancer pathogenesis

2022

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Dystroglycan (DG) is a glycoprotein composed of two subunits that remain non-covalently bound at the plasma membrane: α-DG, which is extracellular and heavily O-mannosyl glycosylated, and β-DG, an integral transmembrane polypeptide. α-DG is involved in the maintenance of tissue integrity and function in the adult, providing an O-glycosylation-dependent link for cells to their extracellular matrix. β-DG in turn contacts the cytoskeleton via dystrophin and participates in a variety of pathways transmitting extracellular signals to the nucleus. Increasing evidence exists of a pivotal role of DG in the modulation of normal cellular proliferation. In this context, deficiencies in DG glycosylation levels, in particular those affecting the so-called matriglycan structure, have been found in an ample variety of human tumors and cancer-derived cell lines. This occurs together with an underexpression of the DAG1 mRNA and/or its α-DG (core) polypeptide product or, more frequently, with a downregulation of β-DG protein levels. These changes are in general accompanied in tumor cells by a low expression of genes involved in the last steps of the α-DG O-mannosyl glycosylation pathway, namely POMT1/2, POMGNT2, CRPPA, B4GAT1 and LARGE1/2. On the other hand, a series of other genes acting earlier in this pathway are overexpressed in tumor cells, namely DOLK, DPM1/2/3, POMGNT1, B3GALNT2, POMK and FKTN, hence exerting instead a pro-oncogenic role. Finally, downregulation of β-DG, altered β-DG processing and/or impaired β-DG nuclear levels are increasingly found in human tumors and cell lines. It follows that DG itself, particular genes/proteins involved in its glycosylation and/or their interactors in the cell could be useful as biomarkers of certain types of human cancer, and/or as molecular targets of new therapies addressing these neoplasms.

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“…Several point mutations within LARGE1 have been known to result in life-threatening phenotypes [24,[26][27][28]. LARGE1 deficiency is also believed to be an underlying cause of epithelium-derived [29] & lung [30] cancers.…”

Section: Introductionmentioning

confidence: 99%

Structural basis for matriglycan synthesis by the LARGE1 dual glycosyltransferase

Katz

Diskin

2022

PLoS ONE

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LARGE1 is a bifunctional glycosyltransferase responsible for generating a long linear polysaccharide termed matriglycan that links the cytoskeleton and the extracellular matrix and is required for proper muscle function. This matriglycan polymer is made with an alternating pattern of xylose and glucuronic acid monomers. Mutations in the LARGE1 gene have been shown to cause life-threatening dystroglycanopathies through the inhibition of matriglycan synthesis. Despite its major role in muscle maintenance, the structure of the LARGE1 enzyme and how it assembles in the Golgi are unknown. Here we present the structure of LARGE1, obtained by a combination of X-ray crystallography and single-particle cryo-EM. We found that LARGE1 homo-dimerizes in a configuration that is dictated by its coiled-coil stem domain. The structure shows that this enzyme has two canonical GT-A folds within each of its catalytic domains. In the context of its dimeric structure, the two types of catalytic domains are brought into close proximity from opposing monomers to allow efficient shuttling of the substrates between the two domains. Together, with putative retention of matriglycan by electrostatic interactions, this dimeric organization offers a possible mechanism for the ability of LARGE1 to synthesize long matriglycan chains. The structural information further reveals the mechanisms in which disease-causing mutations disrupt the activity of LARGE1. Collectively, these data shed light on how matriglycan is synthesized alongside the functional significance of glycosyltransferase oligomerization.

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High LARGE1 Expression May Predict Benefit from Adjuvant Chemotherapy in Resected Non-Small-Cell Lung Cancer

Cited by 4 publications

References 62 publications

Differential expression of glycosyltransferases identified through comprehensive pan-cancer analysis

Differential expression of glycosyltransferases identified through comprehensive pan-cancer analysis

Involvement of abnormal dystroglycan expression and matriglycan levels in cancer pathogenesis

Structural basis for matriglycan synthesis by the LARGE1 dual glycosyltransferase

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