Epigenetic Silencing of the Chaperone Cosmc in Human Leukocytes Expressing Tn Antigen

Mi, Ruifa; Song, Lu; Wang, Yingchun; Ding, Xiaokun; Zeng, Junwei; Lehoux, Sylvain; Aryal, Rajindra P.; Wang, Jianmei; Crew, Vanja Karamatic; Die, Irma van; Chapman, Arlene B.; Cummings, Richard D.; Ju, Tongzhong

doi:10.1074/jbc.m112.371989

Cited by 57 publications

(42 citation statements)

References 54 publications

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“…Recently, hypermethylation in Cosmc, which would result in Cosmc gene silencing, was reported in pancreatic tumours and Tn syndrome expressing truncated O‐glycans 26, 35. We therefore conducted a MALDI‐TOF spectrometry methylation analysis of Cosmc and T‐synthase in another pair of Tn‐positive and Tn‐negative cancer tissues.…”

Section: Resultsmentioning

confidence: 99%

“…The sections were blocked using 0.3% H 2 O 2 and 5% BSA. Then, sections were incubated overnight at 4°C with a specific anti‐Tn IgM monoclonal antibody (5 μg/mL, CA3638, clone 12A8‐C7‐F5, kindly provided by Dr. Tongzhong Ju, Emory University, Atlanta, Georgia, USA)13, 20, 26 followed by horseradish peroxidase‐conjugated antimouse IgM antibody (Abcam, ab97230) for 1 hour at room temperature. Finally, the sections were developed with DAB reagent (ZSGB‐BIO, China) and counterstained with haematoxylin.…”

Section: Methodsmentioning

confidence: 99%

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Aberrant O‐glycosylation contributes to tumorigenesis in human colorectal cancer

Jiang

Liu

et al. 2018

J Cellular Molecular Medi

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Aberrant O‐glycosylation is frequently observed in colorectal cancer (CRC) patients, but it is unclear if it contributes intrinsically to tumorigenesis. Here, we investigated the biological consequences of aberrant O‐glycosylation in CRC. We first detected the expression profile of Tn antigen in a serial of human CRC tissues and then explored the genetic and biosynthetic mechanisms. Moreover, we used a human CRC cell line (LS174T), which express Tn antigen, to assess whether aberrant O‐glycosylation can directly promote oncogenic properties. It showed that Tn antigen was detected in around 86% human primary and metastatic CRC tissues. Bio‐functional investigations showed that T‐synthase and Cosmc were both impaired in cancer tissues. A further analysis detected an occurrence of hypermethylation of Cosmc gene, which possibly caused its loss‐of‐function and a consequent inactive T‐synthase. Transfection of LS174T cells with WT Cosmc restored mature O‐glycosylation, which subsequently down‐regulated cancer cell proliferation, migration and apoptotic‐resistant ability. Significantly, the expression of MUC2, a heavily O‐glycosylated glycoprotein that plays an essential role in intestinal function, was uniformly reduced in human CRC tissues as well as in LS174T cells. These data suggest that aberrant O‐glycosylation contributes to the development of CRC through direct induction of oncogenic properties in cancer cells.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Aberrant O‐glycosylation contributes to tumorigenesis in human colorectal cancer

Jiang

Liu

et al. 2018

J Cellular Molecular Medi

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“…Cosmc mutation is one of the mechanisms that lead to expression of terminal GalNAc (also called Tn antigen) and sialylated GalNAc (also called STn antigen) in cancer. Cosmc may be also downregulated by epigenetic mechanisms (Mi et al, 2013). Notably, the Jurkat cell line with Cosmc mutation reverted to core 1 synthesis when SHIP-1 (Src homology 2-containing inositol 5′-phosphatase-1) was expressed, suggesting that the requirement of Cosmc for the production of active C1GalT1 can be bypassed by another mechanism (Charlier et al, 2010).…”

Section: Biosynthesis Of Iga1 O-glycansmentioning

confidence: 96%

IgA Nephropathy and Related Diseases

et al. 2015

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“…To further characterize the recognition of glycans by VLRs and to examine the utility of VLRs as glycome analysis reagents, we performed a detailed analysis of the glycan binding properties of RBC36 and two additional monoclonal VLRs (O13 and Tn4-22) derived from lampreys immunized with human O erythrocytes or the human B-cell line Tn4 (Mi et al, 2012). Tn4 cells exhibit abnormal cell surface glycosylation profiles, including aberrant expression of the Tn antigen.…”

Section: Introductionmentioning

confidence: 99%

“…Tn4 cells exhibit abnormal cell surface glycosylation profiles, including aberrant expression of the Tn antigen. Thus, to expand the repertoire of glycan-binding VLRs, lamprey were immunized with Tn4 cells (Mi et al, 2012). We used purified recombinant VLRs to quantitatively assess the binding affinities and specificities of these antibodies for glycans.…”

Section: Introductionmentioning

confidence: 99%

Structural Insights into VLR Fine Specificity for Blood Group Carbohydrates

et al. 2017

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SUMMARY High-quality reagents to study and detect glycans with high specificity for research and clinic applications are severely lacking. Here, we structurally and functionally characterize several variable lymphocyte receptor (VLR) based antibodies from lampreys immunized with O erythrocytes that specifically recognize the blood group H-trisaccharide type II antigen. Glycan microarray analysis and biophysical data reveal that these VLRs exhibit greater specificity for H-trisaccharide compared to the plant lectin UEA-1, which is widely used in blood typing. Amongst these antibodies, O13 exhibits superior specificity for H-trisaccharide, the basis for which is revealed by comparative analysis of high-resolution VLR:glycan crystal structures. Using a structure-guided approach, we designed an O13 mutant with further enhanced specificity for H-trisaccharide. These insights into glycan recognition by VLRs suggest that lampreys can produce highly specific glycan antibodies and are a valuable resource for the production of next-generation glycan reagents for biological and biomedical research and as diagnostics and therapeutics.

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Epigenetic Silencing of the Chaperone Cosmc in Human Leukocytes Expressing Tn Antigen

Cited by 57 publications

References 54 publications

Aberrant O‐glycosylation contributes to tumorigenesis in human colorectal cancer

Aberrant O‐glycosylation contributes to tumorigenesis in human colorectal cancer

IgA Nephropathy and Related Diseases

Structural Insights into VLR Fine Specificity for Blood Group Carbohydrates

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