The ST6Gal-I sialyltransferase protects tumor cells against hypoxia by enhancing HIF-1α signaling

Jones, Robert B.; Dorsett, Kaitlyn A.; Hjelmeland, Anita B.; Bellis, Susan L.

doi:10.1074/jbc.ra117.001194

Cited by 65 publications

(57 citation statements)

References 62 publications

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“…Our observations made through the assessment of endogenous expression of ST6GAL1 (which is positively correlated with 2,6-Sial levels), serves to reconcile the contradiction between reports of increased invasion as a result of forced overexpression of ST6GAL1 within cancer cells (24,27) and an overall decreased level of ST6GAL1 expression in breast cancer tissues assessed within The Cancer Genome Atlas (40) . We posit that within a population with heterogeneous expression of α2,6-sialic acids, those with a moderate expression will escape faster through a mesenchymal invasive process.…”

Section: Discussionsupporting

confidence: 58%

“…Several published reports note hypersialylation of cancer cells, including that of the neoplasms of breast (22) cancer. Hypersialylation is associated with, and suggested to be causal to, increased aggressiveness, stemness, resistance to chemotherapeutic agents, ability to survive in stressful conditions like hypoxia and impaired nutrient supply (24,25,27,38). However, when we performed flow cytometry to isolate the two subpopulations showing distinct α2,6 sialic acid levels, the one showing lower levels (which we denoted as medium 2,6-Sial cells) showed greater invasion than high 2,6-Sial cells in both transwell assay and in 3D cultures.…”

Section: Discussionmentioning

confidence: 99%

“…Hypersialylation is one of the most frequently observed changes in glycosylation in many cancer types (22,23). Selective enrichment of terminal α2,6linked sialic acids (referred here-onward as α2,6-Sial), due to overexpression of ST6GAL1, in cancer cell glycocalyces can elicit a wide range of biological outcomes like protection from hypoxia, resistance to chemotherapy, pro-survival and conferral of cancer stem cell phenotype (24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

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ST6GAL1-mediated heterogeneity in sialic acid levels potentiates invasion of breast cancer epithelia

Pally

Pramanik

Hussain

et al. 2020

Preprint

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DP and RB designed the experiments. DP (Pramanik) and RB designed the simulations. DP, SH, SV and AS performed the experiments. DP (Pramanik) performed the simulations. DP, DP (Pramanik) and RB analyzed the data. DP, RB and RK wrote the manuscript. AbstractHeterogeneity in phenotypes of malignantly transformed cells and aberrant glycan expression on their surface are two prominent hallmarks of cancers that have hitherto not been linked to each other. In this paper, we identify heterogeneity in a specific glycan linkage: α2,6-linked sialic acids within breast cancer cells in vivo and in culture. Upon sorting out two populations with moderate and relatively higher cell surface α2,6-linked sialic acid levels from the triple negative breast cancer cell line MDA-MB-231, both populations (denoted as medium and high-2,6-Sial cells respectively) stably retained their levels in early passages. Upon continuous culturing, medium 2,6-Sial cells recapitulated the heterogeneity of the unsorted line whereas high 2,6-Sial cells showed no such tendency. Compared with the high 2,6-Sial, the medium 2,6-Sial cells showed greater adhesion to reconstituted extracellular matrices (ECM) as well as invaded faster as single cells. The level of α2,6-linked sialic acids in the two sublines was found to be consistent with the expression of a specific glycosyl transferase, ST6GAL1. Stably knocking down ST6GAL1 in the high 2,6-Sial cells, enhanced their invasiveness. When cultured together, medium 2,6-Sial cells differentially migrated to the edge of growing tumoroid-like cultures, whereas high 2,6-Sial cells formed the central bulk. Simulations in a Cellular Potts model-based computational environment that is calibrated to our experimental findings suggest that the heterogeneity of cell-ECM adhesion, likely regulated by α2,6-linked sialic acids facilitates niches of highly invasive cells to efficiently migrate centrifugally as the invasive front of a malignant tumor. Significance StatementCell-surface sugars are aberrantly expressed in cancer but their contributions to tumor heterogeneity are not known. In this study, we uncover and separate breast cancer populations with distinct α2,6-linked sialic acid levels. The moderately expressing population shows stronger adhesion to extracellular matrix than the high expressing population. It also invades faster through the matrix as single cells. Combining experiments with computational modelling, we show that the heterogeneity in matrix adhesion is vital to accentuating cell invasion. In some conditions, invasion of heterogeneous populations may compare with, or exceed that of, homogeneous moderately expressing populations. Our findings are vital to furthering our understanding of how cancers spread and potentially qualify efforts to manage the disease through glycan-editing or immunotherapeutic approaches.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ST6GAL1-mediated heterogeneity in sialic acid levels potentiates invasion of breast cancer epithelia

Pally

Pramanik

Hussain

et al. 2020

Preprint

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“…ST6GAL1 levels are upregulated in several carcinomas, as is the degree of α2,6-sialylation (15)(16)(17)(19)(20)(21)(22)(23)(24)(25)(26) (Table I). In particular, elevated ST6GAL1 is often correlated with high tumour grade, metastasis and reduced patient prognosis.…”

Section: Altered St6gal1 In Cancermentioning

confidence: 99%

“…The major determinant of hypoxia mediated angiogenesis is HIF1, a protein capable of upregulating VEGF and PI3K signalling in the absence of oxygen to promote the growth of new vessels (69,70). Hypoxia experiments carried out in ovarian and pancreatic cancer cell lines indicate increased ST6GAL1 expression can lead to an accumulation of HIF1α under hypoxic conditions, as well as increases in HIF1α transcriptional targets (20). These increases suggest upregulated ST6GAL1 confers pro-survival characteristics under hypoxic conditions.…”

Section: St6gal1 In the Hallmarks Of Cancermentioning

confidence: 99%

ST6GAL1: A key player in cancer (Review)

et al. 2019

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Aberrant glycosylation is a universal feature of cancer cells and there is now overwhelming evidence that glycans can modulate pathways intrinsic to tumour cell biology. Glycans are important in all of the cancer hallmarks and there is a renewed interest in the glycomic profiling of tumours to improve early diagnosis, determine patient prognosis and identify targets for therapeutic intervention. One of the most widely occurring cancer associated changes in glycosylation is abnormal sialylation which is often accompanied by changes in sialyltransferase activity. Several sialyltransferases are implicated in cancer, but in recent years ST6 β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) has become increasingly dominant in the literature. ST6GAL1 catalyses the addition of α2,6-linked sialic acids to terminal N-glycans and can modify glycoproteins and/or glycolipids. ST6GAL1 is upregulated in numerous types of cancer (including pancreatic, prostate, breast and ovarian cancer) and can promote growth, survival and metastasis. The present review discusses ST6GAL in relation to the hallmarks of cancer, and highlights its key role in multiple mechanisms intrinsic to tumour cell biology.

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The protective role of endothelial GLUT1 in ischemic stroke

Peng,

Zeng

2024

Brain and Behavior

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ObjectiveTo provide thorough insight on the protective role of endothelial glucose transporter 1 (GLUT1) in ischemic stroke.MethodsWe comprehensively review the role of endothelial GLUT1 in ischemic stroke by narrating the findings concerning biological characteristics of GLUT1 in brain in depth, summarizing the changes of endothelial GLUT1 expression and activity during ischemic stroke, discussing how GLUT1 achieves its neuroprotective effect via maintaining endothelial function, and identifying some outstanding blind spots in current studies.ResultsEndothelial GLUT1 maintains persistent high glucose and energy requirements of the brain by transporting glucose through the blood–brain barrier, which preserves endothelial function and is beneficial to stroke prognosis.ConclusionThis review underscores the potential involvement of GLUT1 trafficking, activity modulation, and degradation, and we look forward to more clinical and animal studies to illuminate these mechanisms.

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The ST6Gal-I sialyltransferase protects tumor cells against hypoxia by enhancing HIF-1α signaling

Cited by 65 publications

References 62 publications

ST6GAL1-mediated heterogeneity in sialic acid levels potentiates invasion of breast cancer epithelia

ST6GAL1-mediated heterogeneity in sialic acid levels potentiates invasion of breast cancer epithelia

ST6GAL1: A key player in cancer (Review)

The protective role of endothelial GLUT1 in ischemic stroke

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