ST6Gal-I sialyltransferase promotes chemoresistance in pancreatic ductal adenocarcinoma by abrogating gemcitabine-mediated DNA damage

Chakraborty, Asmi; Dorsett, Kaitlyn A.; Trummell, Hoa Q.; Yang, Eddy S.; Oliver, Patsy G.; Bonner, James A.; Buchsbaum, Donald J.; Bellis, Susan L.

doi:10.1074/jbc.m117.808584

Cited by 73 publications

(65 citation statements)

References 50 publications

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“…However, α2,6-hypersialylation of fibronectin receptor integrin α5β1 could avoid anoikis by preventing galectin-1 binding to integrins [91,92]. On the other hand, α2,6-sialylation showed vital effects on therapeutic resistance in many cancers [93][94][95], possibly through the sialylated receptors such as EGFR [96][97][98]. EGFR sialylation was reported to suppress its dimerization and to induce phosphorylation, reducing the effects of tyrosine kinase inhibitors [98].…”

Section: Sialic Acids Assist To Resist Apoptosis and Cancer Therapymentioning

confidence: 99%

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

Zhou

Yang

Guan

2020

Cells

131

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Sialic acids, a subset of nine carbon acidic sugars, often exist as the terminal sugars of glycans on either glycoproteins or glycolipids on the cell surface. Sialic acids play important roles in many physiological and pathological processes via carbohydrate-protein interactions, including cell–cell communication, bacterial and viral infections. In particular, hypersialylation in tumors, as well as their roles in tumor growth and metastasis, have been widely described. Recent studies have indicated that the aberrant sialylation is a vital way for tumor cells to escape immune surveillance and keep malignance. In this article, we outline the present state of knowledge on the metabolic pathway of human sialic acids, the function of hypersialylation in tumors, as well as the recent labeling and analytical techniques for sialic acids. It is expected to offer a brief introduction of sialic acid metabolism and provide advanced analytical strategies in sialic acid studies.

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Section: Sialic Acids Assist To Resist Apoptosis and Cancer Therapymentioning

confidence: 99%

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

Zhou

Yang

Guan

2020

Cells

131

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“…Previous studies by our group have demonstrated that exposure of cells to cytotoxic stimuli or cell stressors exerts selective pressure, leading to the expansion of clonal variants with high ST6Gal-I expression (18,19,23,24,36,37). To determine whether this was true in the context of hypoxia, we cultured parental MiaPaCa-2 cells in a hypoxia chamber for 6 weeks to generate a population capable of proliferating under chronic hypoxia ("hypoxia-adapted").…”

Section: St6gal-i Activity Provides a Proliferative Advantage In Hypomentioning

confidence: 99%

“…After the overnight incubation, one set of plates was stained with crystal violet to obtain a baseline value for cell number. The remaining plates were placed into hypoxic culture (0.5% O 2 ) for 24, 48, or 72 h. Subsequently, cells were fixed with 4% paraformaldehyde and then stained with a 0.5% (w/v) crystal violet solution (24). To quantify cell number, the crystal violet-stained cultures were solubilized using a 10% acetic acid solution, and solution absorbance was measured on a Biotek plate reader at 590 nm.…”

Section: Proliferation Assaymentioning

confidence: 99%

“…Recent studies suggest that a central cornerstone of ST6Gal-I's pro-tumorigenic function is its role in conferring a CSC phenotype (18). ST6Gal-I expression correlates with established CSC markers such ALDH1 and CD133 (19), and ST6Gal-I activity imparts hallmark CSC characteristics, including tumor spheroid growth, cell invasiveness, tumor-initiating potential, and resistance to cytotoxic stimuli, including chemotherapeutic drugs (18,(23)(24)(25)(26)(27)(28)(29)(30)(31). ST6Gal-I also promotes epithelial-to-mesenchymal transition (32).…”

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confidence: 99%

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

Jones

Dorsett

Hjelmeland

et al. 2018

Journal of Biological Chemistry

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Aberrant cell surface glycosylation is prevalent in tumor cells, and there is ample evidence that glycans have functional roles in carcinogenesis. Nonetheless, many molecular details remain unclear. Tumor cells frequently exhibit increased α2-6 sialylation on -glycans, a modification that is added by the ST6Gal-I sialyltransferase, and emerging evidence suggests that ST6Gal-I-mediated sialylation promotes the survival of tumor cells exposed to various cell stressors. Here we report that ST6Gal-I protects cancer cells from hypoxic stress. It is well known that hypoxia-inducible factor 1α (HIF-1α) is stabilized in hypoxic cells, and, in turn, HIF-1α directs the transcription of genes important for cell survival. To investigate a putative role for ST6Gal-I in the hypoxic response, we examined HIF-1α accumulation in ovarian and pancreatic cancer cells in ST6Gal-I overexpression or knockdown experiments. We found that ST6Gal-I activity augmented HIF-1α accumulation in cells grown in a hypoxic environment or treated with two chemical hypoxia mimetics, deferoxamine and dimethyloxalylglycine. Correspondingly, hypoxic cells with high ST6Gal-I expression had increased mRNA levels of HIF-1α transcriptional targets, including the glucose transporter genes and and the glycolytic enzyme gene Interestingly, high ST6Gal-I-expressing cells also had an increased pool of HIF-1α mRNA, suggesting that ST6Gal-I may influence HIF-1α expression. Finally, cells grown in hypoxia for several weeks displayed enriched ST6Gal-I expression, consistent with a pro-survival function. Taken together, these findings unravel a glycosylation-dependent mechanism that facilitates tumor cell adaptation to a hypoxic milieu.

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“…ST6Gal-I regulates tumor cell phenotype by modulating the sialylation, and therefore function, of key receptors that drive malignant cell behaviors [11][12][13][14][15][16][17]. We and others have shown that ST6Gal-I activity confers all of the hallmark features of a CSC including increased expression of canonical CSC markers [18], invasive potential [16,19], tumor-initiating potential [9,20], and resistance to hypoxia, chemotherapeutics, and radiation [14,[20][21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 97%

Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells

et al. 2019

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Background: The ST6Gal-I glycosyltransferase, which adds α2-6-linked sialic acids to N-glycosylated proteins is upregulated in a wide range of malignancies including ovarian cancer. Prior studies have shown that ST6Gal-Imediated sialylation of select surface receptors remodels intracellular signaling to impart cancer stem cell (CSC) characteristics. However, the mechanisms that contribute to ST6Gal-I expression in stem-like cancer cells are poorly understood. Results: Herein, we identify the master stem cell transcription factor, Sox2, as a novel regulator of ST6Gal-I expression. Interestingly, SOX2 and ST6GAL1 are located within the same tumor-associated amplicon, 3q26, and these two genes exhibit coordinate gains in copy number across multiple cancers including~25% of ovarian serious adenocarcinomas. In conjunction with genetic co-amplification, our studies suggest that Sox2 directly binds the ST6GAL1 promoter to drive transcription. ST6Gal-I expression is directed by at least four distinct promoters, and we identified the P3 promoter as the predominant promoter utilized by ovarian cancer cells. Chromatin Immunoprecipitation (ChIP) assays revealed that Sox2 binds regions proximal to the P3 promoter. To confirm that Sox2 regulates ST6Gal-I expression, Sox2 was either overexpressed or knocked-down in various ovarian cancer cell lines. Sox2 overexpression induced an increase in ST6Gal-I mRNA and protein, as well as surface α2-6 sialylation, whereas Sox2 knock-down suppressed levels of ST6Gal-I mRNA, protein and surface α2-6 sialylation. Conclusions: These data suggest a process whereby SOX2 and ST6GAL1 are coordinately amplified in cancer cells, with the Sox2 protein then binding the ST6GAL1 promoter to further augment ST6Gal-I expression. Our collective results provide new insight into mechanisms that upregulate ST6Gal-I expression in ovarian cancer cells, and also point to the possibility that some of the CSC characteristics commonly attributed to Sox2 may, in part, be mediated through the sialyltransferase activity of ST6Gal-I.

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ST6Gal-I sialyltransferase promotes chemoresistance in pancreatic ductal adenocarcinoma by abrogating gemcitabine-mediated DNA damage

Cited by 73 publications

References 50 publications

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

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

Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells

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