Analysis of the proximal promoter of the human colon-specific B4GALNT2 (Sda synthase) gene: B4GALNT2 is transcriptionally regulated by ETS1

Wavelet-Vermuse, Cindy; Groux-Degroote, Sophie; Vicogne, Dorothée; Cogez, Virginie; Venturi, Giulia; Trinchera, Marco; Brysbaert, Guillaume; Krzewinski-Recchi, Marie-Ange; Bachir, Elsa Hadj; Schulz, Céline; Vincent, Audrey; Seuningen, Isabelle Van; Harduin-Lepers, Anne

doi:10.1016/j.bbagrm.2021.194747

Cited by 5 publications

(4 citation statements)

References 64 publications

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“…Such regions can stretch much further than what has been investigated here and, in the case of Cad, it would be of interest to search systematically for enhancer elements. Methylation in areas of the gene and the transcription factors ETS1 and SP1 have been associated with regulation of B4GALNT2 in malignant colon tissue [ 30 , 31 , 32 ] However, it is not known how this may affect Sd a expression on erythrocytes. Among the Cad samples (Cad-a and Cad-b), it was interesting to see that one individual was heterozygous for rs72835417:G>A, the splice-site mutation in intron 8, found earlier heterozygously in two Sd(a−) individuals (1,2), and thereby suggested as a reason to lack the antigen.…”

Section: Discussionmentioning

confidence: 99%

Glycoproteomic and Phenotypic Elucidation of B4GALNT2 Expression Variants in the SID Histo-Blood Group System

Stenfelt

Nilsson

Hellberg³

et al. 2022

IJMS

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The Sda histo-blood group antigen (GalNAcβ1-4(NeuAcα2-3)Galβ-R) is implicated in various infections and constitutes a potential biomarker for colon cancer. Sd(a−) individuals (2–4% of Europeans) may produce anti-Sda, which can lead to incompatible blood transfusions, especially if donors with the high-expressing Sd(a++)/Cad phenotype are involved. We previously reported the association of B4GALNT2 mutations with Sd(a−), which established the SID blood-group system. The present study provides causal proof underpinning this correlation. Sd(a−) HEK293 cells were transfected with different B4GALNT2 constructs and evaluated by immunostaining and glycoproteomics. The predominant SIDnull candidate allele with rs7224888:T>C (p.Cys406Arg) abolished Sda synthesis, while this antigen was detectable as N- or O-glycans on glycoproteins following transfection of wildtype B4GALNT2. Surprisingly, two rare missense variants, rs148441237:A>G and rs61743617:C>T, found in a Sd(a−) compound heterozygote, gave results similar to wildtype. To elucidate on whether Sd(a++)/Cad also depends on B4GALNT2 alterations, this gene was sequenced in five individuals. No Cad-specific changes were identified, but a detailed erythroid Cad glycoprotein profile was obtained, especially for glycophorin-A (GLPA) O-glycosylation, equilibrative nucleoside transporter 1 (S29A1) O-glycosylation, and band 3 anion transport protein (B3AT) N-glycosylation. In conclusion, the p.Cys406Arg β4GalNAc-T2 variant causes Sda-deficiency in humans, while the enigmatic Cad phenotype remains unresolved, albeit further characterized.

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Section: Discussionmentioning

confidence: 99%

Glycoproteomic and Phenotypic Elucidation of B4GALNT2 Expression Variants in the SID Histo-Blood Group System

Stenfelt

Nilsson

Hellberg³

et al. 2022

IJMS

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“…A weak expression of the B4GALNT2 transcript and of the Sd a antigen was induced by treatment of cell lines with anti-DNA-methylation agents [ 30 ]. Recently, it has been shown that the transcription factors ETS1 and, to a lesser extent, SP1 are required for B4GALNT2 transcription, although neither of the two is responsible for its differential expression in CRC [ 31 ].…”

Section: The Sd a Antigen: Structure And Biosynthesismentioning

confidence: 99%

The Cancer-Associated Antigens Sialyl Lewisa/x and Sda: Two Opposite Faces of Terminal Glycosylation

Dall’Olio

Pucci

Malagolini

2021

Cancers

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Terminal carbohydrate structures are particularly relevant in oncology because they can serve as cancer markers and alter the phenotype of cancer cells. The Sda antigen and the sialyl Lewisx and sialyl Lewisa (sLex and sLea) antigens are terminal structures whose biosynthesis is mutually exclusive. In this review, we describe the main features of the Sda antigen in cancer and its relationship with sLex/a antigens. Information was obtained from an extensive literature search and from The Cancer Genome Atlas (TCGA) public database. The Sda biosynthetic enzyme B4GALNT2 undergoes downregulation in colorectal (CRC) and stomach cancer, while it is ectopically expressed by a minority of breast cancer (BRCA) patients. High expression of B4GALNT2 is associated with better prognosis and a less malignant gene expression profile in CRC, while the opposite occurs in BRCA. The regulation of B4GALNT2 expression in CRC is multifactorial, involving gene methylation and miRNA expression. Forced expression of B4GALNT2 inhibited sLea/sLex and reduced malignancy and stemness in cells constitutively expressing sLex/a antigens. However, consistent effects were observed upon B4GALNT2 forced expression and in cells not expressing sLex/a antigens. Thus, B4GALNT2 and the Sda antigen exert a tumor-restraining activity in CRC and probably other gastrointestinal cancers, independently of sLex/a antigens.

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“…Another crucial role in B4GALNT2 regulation can be played by transcription factors. The transcription factors ETS1 and, to a lesser extent, SP1 are necessary for gene transcription, although their different expression does not appear to be responsible for B4GALNT2 modulation in pathological conditions, such as colon cancer (see below) [20].…”

Section: Introductionmentioning

confidence: 99%

The Sda Carbohydrate Antigen and Its Biosynthetic Enzyme B4GALNT2 in Health and Disease.

Duca,

Malagolini,

Dall’Olio

2024

Preprint

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The carbohydrate antigen Sda is expressed on cells and secretions of the vast majority of Caucasians. The epitope is formed by a terminal GalNAc residue β4-linked to a α3-sialylated galactose. Different carbohydrate chains N- or O-linked to glycoproteins can be terminated by this epitope. The final step of Sda biosynthesis is catalyzed by the GalNAc transferase B4GALNT2. In this review, we will discuss the multifaceted aspects of B4GALNT2/Sda biology. In particular, we will see its implications in fertility and pregnancy, in susceptibility to infectious diseases, in chronic kidney diseases and in Duchene muscular dystrophy. In particular, we will show its regulation and prognostic implications in cancer.

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Analysis of the proximal promoter of the human colon-specific B4GALNT2 (Sda synthase) gene: B4GALNT2 is transcriptionally regulated by ETS1

Cited by 5 publications

References 64 publications

Glycoproteomic and Phenotypic Elucidation of B4GALNT2 Expression Variants in the SID Histo-Blood Group System

Glycoproteomic and Phenotypic Elucidation of B4GALNT2 Expression Variants in the SID Histo-Blood Group System

The Cancer-Associated Antigens Sialyl Lewisa/x and Sda: Two Opposite Faces of Terminal Glycosylation

The Sda Carbohydrate Antigen and Its Biosynthetic Enzyme B4GALNT2 in Health and Disease.

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