Regulation of inflammatory signaling by the ST6Gal-I sialyltransferase

Holdbrooks, Andrew T.; Ankenbauer, Katherine E; Hwang, Jin Ha; Bellis, Susan L.

doi:10.1371/journal.pone.0241850

Cited by 18 publications

(15 citation statements)

References 48 publications

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“…Diabetics are at an increased risk of developing HFS and we confirmed an association for ST6GAL1 with T2D, and also found that rs6783836 was associated with glycated haemoglobin levels, a marker routinely used in the diagnosis and monitoring of diabetes, supporting an interrelationship. ST6GAL1 has a known role in inflammation 31 and we found an association between rs6783836 and lymphocyte count and psoriasis. Given that others have associated ST6GAL1 with psoriasis in an Asian population, 32 these data support a link between these syndromes and an underlying defect in the inflammatory pathway.…”

Section: Discussionsupporting

confidence: 50%

Genetic variation in ST6GAL1 is a determinant of capecitabine and oxaliplatin induced hand‐foot syndrome

Watts

Wills

Madi

et al. 2022

Intl Journal of Cancer

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Cancer patients treated with capecitabine and oxaliplatin (XELOX) often develop hand‐foot syndrome (HFS) or palmar‐plantar erythrodysesthesia. Genetic variation in ST6GAL1 is a risk factor for type‐2 diabetes (T2D), a disease also associated with HFS. We analysed genome‐wide association data for 10 toxicities in advanced colorectal cancer (CRC) patients from the COIN and COIN‐B trials. One thousand and fifty‐five patients were treated with XELOX ± cetuximab and 745 with folinic acid, fluorouracil and oxaliplatin ± cetuximab. We also analysed rs6783836 in ST6GAL1 with HFS in CRC patients from QUASAR2. Using UK Biobank data, we sought to confirm an association between ST6GAL1 and T2D (17 384 cases, 317 887 controls) and analysed rs6783836 against markers of diabetes, inflammation and psoriasis. We found that 68% of patients from COIN and COIN‐B with grade 2‐3 HFS responded to treatment as compared to 58% with grade 0‐1 HFS (odds ratio [OR] = 1.1, 95% confidence interval [CI] = 1.02‐1.2, P = 2.0 × 10−4). HFS was also associated with improved overall survival (hazard ratio = 0.92, 95% CI = 0.84‐0.99, P = 4.6 × 10−2). rs6783836 at ST6GAL1 was associated with HFS in patients treated with XELOX (OR = 3.1, 95% CI = 2.1‐4.6, P = 4.3 × 10−8) and was borderline significant in patients receiving capecitabine from QUASAR2, but with an opposite allele effect (OR = 0.66, 95% CI = 0.42‐1.03, P = .05). ST6GAL1 was associated with T2D (lead SNP rs3887925, OR = 0.94, 95% CI = 0.92‐0.96, P = 1.2 × 10−8) and the rs6783836‐T allele was associated with lowered HbA1c levels (P = 5.9 × 10−3) and lymphocyte count (P = 2.7 × 10−3), and psoriasis (P = 7.5 × 10−3) beyond thresholds for multiple testing. In conclusion, HFS is a biomarker of treatment outcome and rs6783836 in ST6GAL1 is a potential biomarker for HFS with links to T2D and inflammation.

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Section: Discussionsupporting

confidence: 50%

Genetic variation in ST6GAL1 is a determinant of capecitabine and oxaliplatin induced hand‐foot syndrome

Watts

Wills

Madi

et al. 2022

Intl Journal of Cancer

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“…These opposing functions of protein sialylation depend upon the target substrate molecules and the locations where the modification is regulated. Recent studies in mice using BM transplantation or monocyte-specific Cre-LoxP system have uncovered the key function of neuraminidases and sialyltransferases in monocytes and macrophages ( 80 , 90 , 94 , 120 , 123 ). More studies are needed to address the importance of protein sialylation using mice with additional tissue- and cell-type-specific targeting of the machinery, including endothelial cells and vascular smooth muscle cells.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, Holdbrooks et al. showed that BM-derived macrophages from mice with myeloid-specific St6Gal1 deletion display reduced long-term activation of nuclear factor kappa B (NF-kB) by TNFα or lipopolysaccharide (LPS) ( 120 ). Furthermore, in experiments using cultured monocytes, the study implicates TNFR1 or TLR4 to be a potential substrate of St6Gal1-mediated α2-6 sialylation related to the inflammatory regulation by monocytes/macrophages.…”

Section: Mouse Models Of Sialylation and Atherosclerosismentioning

confidence: 99%

Lipoprotein sialylation in atherosclerosis: Lessons from mice

Peng

Mineo

2022

Front. Endocrinol.

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Sialylation is a dynamically regulated modification, which commonly occurs at the terminal of glycan chains in glycoproteins and glycolipids in eukaryotic cells. Sialylation plays a key role in a wide array of biological processes through the regulation of protein–protein interactions, intracellular localization, vesicular trafficking, and signal transduction. A majority of the proteins involved in lipoprotein metabolism and atherogenesis, such as apolipoproteins and lipoprotein receptors, are sialylated in their glycan structures. Earlier studies in humans and in preclinical models found a positive correlation between low sialylation of lipoproteins and atherosclerosis. More recent works using loss- and gain-of-function approaches in mice have revealed molecular and cellular mechanisms by which protein sialylation modulates causally the process of atherosclerosis. The purpose of this concise review is to summarize these findings in mouse models and to provide mechanistic insights into lipoprotein sialylation and atherosclerosis.

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“…Although ST6Gal1 is thought to be the main enzyme responsible for the bulk of N-glycoprotein-linked a2-6 sialylation, mice with total St6gal1 knockout are viable, with a surprisingly mild phenotype mainly manifest in immune cell function: increased inflammation, defects in dendritic cell, and myelopoiesis, as well as mature B-cell development (50)(51)(52). Also, the phenotype of mice with specific knockout of St6gal1 in the liver, an organ with particularly high ST6Gal1 expression, is mild (32).…”

Section: St6gal1 a Non-essential Protein With Unique Enzymatic Activi...mentioning

confidence: 99%

Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia

Zhang

Yang

et al. 2022

Front. Oncol.

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Normal early human B-cell development from lymphoid progenitors in the bone marrow depends on instructions from elements in that microenvironment that include stromal cells and factors secreted by these cells including the extracellular matrix. Glycosylation is thought to play a key role in such interactions. The sialyltransferase ST6Gal1, with high expression in specific hematopoietic cell types, is the only enzyme thought to catalyze the terminal addition of sialic acids in an α2-6-linkage to galactose on N-glycans in such cells. Expression of ST6Gal1 increases as B cells undergo normal B-lineage differentiation. B-cell precursor acute lymphoblastic leukemias (BCP-ALLs) with differentiation arrest at various stages of early B-cell development have widely different expression levels of ST6GAL1 at diagnosis, with high ST6Gal1 in some but not in other relapses. We analyzed the consequences of increasing ST6Gal1 expression in a diagnosis sample using lentiviral transduction. NSG mice transplanted with these BCP-ALL cells were monitored for survival. Compared to mice transplanted with leukemia cells expressing original ST6Gal1 levels, increased ST6Gal1 expression was associated with significantly reduced survival. A cohort of mice was also treated for 7 weeks with vincristine chemotherapy to induce remission and then allowed to relapse. Upon vincristine discontinuation, relapse was detected in both groups, but mice transplanted with ST6Gal1 overexpressing BCP-ALL cells had an increased leukemia burden and shorter survival than controls. The BCP-ALL cells with higher ST6Gal1 were more resistant to long-term vincristine treatment in an ex vivo tissue co-culture model with OP9 bone marrow stromal cells. Gene expression analysis using RNA-seq showed a surprisingly large number of genes with significantly differential expression, of which approximately 60% increased mRNAs, in the ST6Gal1 overexpressing BCP-ALL cells. Pathways significantly downregulated included those involved in immune cell migration. However, ST6Gal1 knockdown cells also showed increased insensitivity to chemotherapy. Our combined results point to a context-dependent effect of ST6Gal1 expression on BCP-ALL cells, which is discussed within the framework of its activity as an enzyme with many N-linked glycoprotein substrates.

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Regulation of inflammatory signaling by the ST6Gal-I sialyltransferase

Cited by 18 publications

References 48 publications

Genetic variation in ST6GAL1 is a determinant of capecitabine and oxaliplatin induced hand‐foot syndrome

Genetic variation in ST6GAL1 is a determinant of capecitabine and oxaliplatin induced hand‐foot syndrome

Lipoprotein sialylation in atherosclerosis: Lessons from mice

Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia

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