Epigenetic Regulation of Glycosylation in Cancer and Other Diseases

Indellicato, Rossella; Trinchera, Marco

doi:10.3390/ijms22062980

Cited by 13 publications

(9 citation statements)

References 156 publications

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“…Aging in general leads to epigenetic mediated deregulation of genes so it is safe to assume that the glycan clock heritability estimates are not devoid of this effect ( Saldanha and Watanabe, 2015 ). Different studies reported that the process of protein glycosylation is under strong epigenetic control ( Horvat et al, 2013 ; Agrawal et al, 2014 ; Greville et al, 2016 , 2021 ; Indellicato and Trinchera, 2021 ). We hypothesize that aging related epigenetic changes such as altered DNA methylation, abnormal chromatin state, altered histone modifications and deregulation of non-coding RNAs ( Saldanha and Watanabe, 2015 ) also impact the glycan clock variation which is reflected in the inflated heritability estimates after age correction.…”

Section: Discussionmentioning

confidence: 99%

Heritability of the glycan clock of biological age

Mijakovac

Frkatović²,

Ivok³

et al. 2022

Front. Cell Dev. Biol.

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Immunoglobulin G is posttranslationally modified by the addition of complex N-glycans affecting its function and mediating inflammation at multiple levels. IgG glycome composition changes with age and health in a predictive pattern, presumably due to inflammaging. As a result, a novel biological aging biomarker, glycan clock of age, was developed. Glycan clock of age is the first of biological aging clocks for which multiple studies showed a possibility of clock reversal even with simple lifestyle interventions. However, none of the previous studies determined to which extent the glycan clock can be turned, and how much is fixed by genetic predisposition. To determine the contribution of genetic and environmental factors to phenotypic variation of the glycan clock, we performed heritability analysis on two TwinsUK female cohorts. IgG glycans from monozygotic and dizygotic twin pairs were analyzed by UHPLC and glycan age was calculated using the glycan clock. In order to determine additive genetic, shared, and unique environmental contributions, a classical twin design was applied. Heritability of the glycan clock was calculated for participants of one cross-sectional and one longitudinal cohort with three time points to assess the reliability of measurements. Heritability estimate for the glycan clock was 39% on average, suggesting a moderate contribution of additive genetic factors (A) to glycan clock variation. Remarkably, heritability estimates remained approximately the same in all time points of the longitudinal study, even though IgG glycome composition changed substantially. Most environmental contributions came from shared environmental factors (C), with unique environmental factors (E) having a minor role. Interestingly, heritability estimates nearly doubled, to an average of 71%, when we included age as a covariant. This intervention also inflated the estimates of unique environmental factors contributing to glycan clock variation. A complex interplay between genetic and environmental factors defines alternative IgG glycosylation during aging and, consequently, dictates the glycan clock’s ticking. Apparently, environmental factors (including lifestyle choices) have a strong impact on the biological age measured with the glycan clock, which additionally clarifies why this aging clock is one of the most potent biomarkers of biological aging.

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Section: Discussionmentioning

confidence: 99%

Heritability of the glycan clock of biological age

Mijakovac

Frkatović²,

Ivok³

et al. 2022

Front. Cell Dev. Biol.

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“…Here, we observed the transcriptional upregulation of TRAIL receptors and enzymes involved in O-glycosylation, such as GALNT14, C1GALT1, and C1GALT1C1. The expression of these molecules is regulated by multiple mechanisms, including transcription factors, epigenetic modifications, and miRNAs [54,55]. Therefore, proscillaridin A may upregulate TRAIL receptor expression and O-glycosylation by affecting multiple pathways, including histone acetylation and MYC expression.…”

Section: Discussionmentioning

confidence: 99%

Proscillaridin A Sensitizes Human Colon Cancer Cells to TRAIL-Induced Cell Death

Semba

Takamatsu

Komazawa-Sakon

et al. 2022

IJMS

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytotoxic cytokine that induces cancer cell death by binding to TRAIL receptors. Because of its selective cytotoxicity toward cancer cells, TRAIL therapeutics, such as recombinant TRAIL and agonistic antibodies targeting TRAIL receptors, have garnered attention as promising cancer treatment agents. However, many cancer cells acquire resistance to TRAIL-induced cell death. To overcome this issue, we searched for agents to sensitize cancer cells to TRAIL-induced cell death by screening a small-molecule chemical library consisting of diverse compounds. We identified a cardiac glycoside, proscillaridin A, as the most effective TRAIL sensitizer in colon cancer cells. Proscillaridin A synergistically enhanced TRAIL-induced cell death in TRAIL-sensitive and -resistant colon cancer cells. Additionally, proscillaridin A enhanced cell death in cells treated with TRAIL and TRAIL sensitizer, the second mitochondria-derived activator of caspase mimetic. Proscillaridin A upregulated TRAIL receptor expression, while downregulating the levels of the anti-cell death molecules, cellular FADD-like IL-1β converting enzyme-like inhibitor protein and Mcl1, in a cell type-dependent manner. Furthermore, proscillaridin A enhanced TRAIL-induced cell death partly via O-glycosylation. Taken together, our findings suggest that proscillaridin A is a promising agent that enhances the anti-cancer efficacy of TRAIL therapeutics.

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“…23,24 Aberrant glycosylation patterns have been linked to the development of several diseases, including genetic diseases, neurodegenerative diseases, and cancer. 25,26 Recent reports have also linked altered glycosylation expression to the development of breast cancer and cerebral metastases. 17,27−29 The serum biomarker most commonly utilized in breast cancer patients is Cancer antigen (CA) 15-3 and its effectiveness is attributed to the increased expression and altered glycosylation state of MUC-1.…”

Section: Introductionmentioning

confidence: 99%

“…N - and O -linked glycosylation are the two most significant types of protein glycosylation. Membrane glycome and secreted glycoproteins are essential in several physiological processes, including cell signaling, communication, and adhesion. − Also, protein glycosylation is vital in modulating protein folding, stability, structure, and function. , Aberrant glycosylation patterns have been linked to the development of several diseases, including genetic diseases, neurodegenerative diseases, and cancer. , Recent reports have also linked altered glycosylation expression to the development of breast cancer and cerebral metastases. ,− The serum biomarker most commonly utilized in breast cancer patients is Cancer antigen (CA) 15-3 and its effectiveness is attributed to the increased expression and altered glycosylation state of MUC-1. − MUC-1 is an extensively O -glycosylated protein and changes in its expression have been linked to the development of cancer and metastasis. − Therefore, it is important to perform O -glycan profiling to understand the changes that may be involved in BCBM.…”

Section: Introductionmentioning

confidence: 99%

O-Glycome Profiling of Breast Cancer Cell Lines to Understand Breast Cancer Brain Metastasis

Onigbinde,

Peng,

Reddy

et al. 2024

J. Proteome Res.

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Breast cancer is the second leading cause of cancer-related death among women and a major source of brain metastases. Despite the increasing incidence of brain metastasis from breast cancer, the underlying mechanisms remain poorly understood. Altered glycosylation is known to play a role in various diseases including cancer metastasis. However, profiling studies of O-glycans and their isomers in breast cancer brain metastasis (BCBM) are scarce. This study analyzed the expression of O-glycans and their isomers in human breast cancer cell lines (MDA-MB-231, MDA-MB-361, HTB131, and HTB22), a brain cancer cell line (CRL-1620), and a brain metastatic breast cancer cell line (MDA-MB-231BR) using nanoLC-MS/MS, identifying 27 O-glycan compositions. We observed significant upregulation in the expression of HexNAc 1 Hex 1 NeuAc 2 and HexNAc 2 Hex 3 , whereas the expression of HexNAc 1 Hex 1 NeuAc 1 was downregulated in MDA-MB-231BR compared to other cell lines. In our isomeric analysis, we observed notable alterations in the isomeric forms of the O-glycan structure HexNAc 1 Hex 1 NeuAc 1 in a comparison of different cell lines. Our analysis of Oglycans and their isomers in cancer cells demonstrated that changes in their distribution can be related to the metastatic process. We believe that our investigation will contribute to an enhanced comprehension of the significance of O-glycans and their isomers in BCBM.

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Epigenetic Regulation of Glycosylation in Cancer and Other Diseases

Cited by 13 publications

References 156 publications

Heritability of the glycan clock of biological age

Heritability of the glycan clock of biological age

Proscillaridin A Sensitizes Human Colon Cancer Cells to TRAIL-Induced Cell Death

O-Glycome Profiling of Breast Cancer Cell Lines to Understand Breast Cancer Brain Metastasis

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