Silencing of ST6Gal I enhances colorectal cancer metastasis by down-regulating KAI1 via exosome-mediated exportation and thereby rescues integrin signaling

Jung, Yu Ri; Park, Jung-Jin; Jin, Yeung Bae; Cao, Yuan; Park, Myungjin; Kim, Sang Hyun; Lee, Minyoung

doi:10.1093/carcin/bgw091

Cited by 22 publications

(17 citation statements)

References 53 publications

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“…The effect of specific N-glycosylation events varies, with some promoting tumor progression, while others limit progression/metastases. Elevated expression of ST6GAL1 has previously been observed in multiple types of adenocarcinomas and linked to both worsened and improved outcomes (57,58). These contradictory observations may relate to differences in cancer mucin expression and/or effect on PI3K/Akt-related proliferation pathways (59,60).…”

Section: Discussionmentioning

confidence: 97%

Sialylation of MUC4β N-glycans by ST6GAL1 orchestrates human airway epithelial cell differentiation associated with type-2 inflammation

Zhou¹,

Kinlough²,

Hughey³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 97%

Sialylation of MUC4β N-glycans by ST6GAL1 orchestrates human airway epithelial cell differentiation associated with type-2 inflammation

Zhou¹,

Kinlough²,

Hughey³

et al. 2019

JCI Insight

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“…Previous studies have indicated a correlation between ST6Gal-I activity and cancer metastasis, while in others such correlation has not been found [46]. There are also other studies, showing that ST6Gal-I overexpression changes cellular phenotype or behavior, e.g.…”

Section: Resultsmentioning

confidence: 99%

“…Sialylation regulates numerous cellular processes, including cell–cell communication, immune surveillance, defense against pathogens and cancer progression and metastasis [46,53]. In cancers, especially α-2,6-sialylation is increased and correlates with increased cell proliferation, migration, invasion and metastasis, while inhibiting apoptosis [[47], [48], [49], [50]].…”

Section: Discussionmentioning

confidence: 99%

A Golgi-associated redox switch regulates catalytic activation and cooperative functioning of ST6Gal-I with B4GalT-I

et al. 2019

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Glycosylation, a common modification of cellular proteins and lipids, is often altered in diseases and pathophysiological states such as hypoxia, yet the underlying molecular causes remain poorly understood. By utilizing lectin microarray glycan profiling, Golgi pH and redox screens, we show here that hypoxia inhibits terminal sialylation of N- and O-linked glycans in a HIF- independent manner by lowering Golgi oxidative potential. This redox state change was accompanied by loss of two surface-exposed disulfide bonds in the catalytic domain of the α-2,6-sialyltransferase (ST6Gal-I) and its ability to functionally interact with B4GalT-I, an enzyme adding the preceding galactose to complex N-glycans. Mutagenesis of selected cysteine residues in ST6Gal-I mimicked these effects, and also rendered the enzyme inactive. Cells expressing the inactive mutant, but not those expressing the wild type ST6Gal-I, were able to proliferate and migrate normally, supporting the view that inactivation of the ST6Gal-I help cells to adapt to hypoxic environment. Structure comparisons revealed similar disulfide bonds also in ST3Gal-I, suggesting that this O-glycan and glycolipid modifying sialyltransferase is also sensitive to hypoxia and thereby contribute to attenuated sialylation of O-linked glycans in hypoxic cells. Collectively, these findings unveil a previously unknown redox switch in the Golgi apparatus that is responsible for the catalytic activation and cooperative functioning of ST6Gal-I with B4GalT-I.

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“…They export the protein via EVs, as indicated by EVs that are more enriched in PABP1 as compared to EVs from normal AZ-521 cells. Colorectal cancer cells were also found to export, KAI1 (CD82), a suppressor of tumor metastasis, via EVs as a cell-autonomous mechanism to enhance metastasis [71–74]. However, further exploration of this mechanism is necessary to develop therapeutics that can inhibit EV-mediated secretion of tumor suppressors.…”

Section: Role Of Ev Cargo In Metastatic Processesmentioning

confidence: 99%

The key role of extracellular vesicles in the metastatic process

Zhao

Achreja

Iessi

et al. 2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

125

147

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Extracellular vesicles (EVs), including exosomes, have a key role in the paracrine communication between organs and compartments. EVs shuttle virtually all types of biomolecules such as proteins, lipids, nucleic acids, metabolites and even pharmacological compounds. Their ability to transfer their biomolecular cargo into target cells enables EVs to play a key role in intercellular communication that can regulate cellular functions such as proliferation, apoptosis and migration. This has led to the emergence of EVs as a key player in tumor growth and metastasis through the formation of "tumor niches" in target organs. Recent data have also been shown that EVs may transform the microenvironment of primary tumors thus favoring the selection of cancer cells with a metastatic behavior. The release of EVs from resident non-malignant cells may contribute to the metastatic processes as well. However, cancer EVs may induce malignant transformation in resident mesenchymal stem cells, suggesting that the metastatic process is not exclusively due to circulating tumor cells. In this review, we outline and discuss evidence-based roles of EVs in actively regulating multiple steps of the metastatic process and how we can leverage EVs to impair metastasis.

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Silencing of ST6Gal I enhances colorectal cancer metastasis by down-regulating KAI1 via exosome-mediated exportation and thereby rescues integrin signaling

Cited by 22 publications

References 53 publications

Sialylation of MUC4β N-glycans by ST6GAL1 orchestrates human airway epithelial cell differentiation associated with type-2 inflammation

Sialylation of MUC4β N-glycans by ST6GAL1 orchestrates human airway epithelial cell differentiation associated with type-2 inflammation

A Golgi-associated redox switch regulates catalytic activation and cooperative functioning of ST6Gal-I with B4GalT-I

The key role of extracellular vesicles in the metastatic process

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