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Review
. 2021 Jun 3;31(5):530-539.
doi: 10.1093/glycob/cwaa110.

Regulation of ST6GAL1 sialyltransferase expression in cancer cells

Kaitlyn A Dorsett  1 , Michael P Marciel  1 , Jihye Hwang  1 , Katherine E Ankenbauer  1 , Nikita Bhalerao  1 , Susan L Bellis  1
Affiliations
Review

Regulation of ST6GAL1 sialyltransferase expression in cancer cells

Kaitlyn A Dorsett et al. Glycobiology. .

Abstract

The ST6GAL1 sialyltransferase, which adds α2-6 linked sialic acids to N-glycosylated proteins, is overexpressed in a wide range of human malignancies. Recent studies have established the importance of ST6GAL1 in promoting tumor cell behaviors such as invasion, resistance to cell stress and chemoresistance. Furthermore, ST6GAL1 activity has been implicated in imparting cancer stem cell characteristics. However, despite the burgeoning interest in the role of ST6GAL1 in the phenotypic features of tumor cells, insufficient attention has been paid to the molecular mechanisms responsible for ST6GAL1 upregulation during neoplastic transformation. Evidence suggests that these mechanisms are multifactorial, encompassing genetic, epigenetic, transcriptional and posttranslational regulation. The purpose of this review is to summarize current knowledge regarding the molecular events that drive enriched ST6GAL1 expression in cancer cells.

Keywords: ST6GAL1; cancer; gene regulation; sialic acid.

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Figures

Fig. 1
Fig. 1
ST6GAL1 expression in normal and malignant pancreatic tissues. ST6GAL1 protein expression was evaluated by IHC in pancreatic tissues using a well-validated antibody, as in our prior studies (Swindall et al. 2013; Schultz et al. 2016). (A) No detectable ST6Gal-I expression was observed in normal pancreatic acinar cells (red inset); however, a subset of cells within the islets (blue inset) expresses ST6GAL1. Scale bar = 50 μM. (B) Left panel: co-staining for ST6GAL1 (red) and insulin (green) in wild-type mice confirms that ST6GAL1 is expressed in the β cells of the islets. Right panel, no ST6GAL1-positive cells are detected in the islets of St6gal1 KO mice, verifying specificity of the antibody. Scale bars = 25 μM. (C) In ductal-like malignant lesions, ST6GAL1expression is found on the luminal side of the nucleus, consistent with Golgi localization. Scale bar = 50 μM. (D) In non-ductal-like malignant lesions, ST6GAL1 staining often presents as multiple punctae within cancer cells (arrowheads), whereas staining in immune/stromal cells typically appears as a single spot adjacent to the nucleus (arrows). Scale bar = 50 μM. (E) ST6GAL1 (red) is co-expressed with Sox9 (green), a known tumor cell marker (arrowheads). ST6GAL1 is also found in immune cells (arrows), illustrated by co-staining with the immune marker CD45 (yellow). Scale bar = 50 μM. This figure is available in black and white in print and in colour at Glycobiology online.
Fig. 2
Fig. 2
Gene amplification of ST6GAL1 in multiple human cancers. TCGA databases were evaluated using cBioportal (Cerami et al. 2012) for ST6GAL1 mutations or changes in ST6GAL1 copy number. Amplifications are denoted in red, mutations in green and deletions in blue. Each vertical bar represents a distinct cancer cohort, with the first three bars on the left representing lung squamous cell carcinomas, and the fourth bar, ovarian serous adenocarcinoma. Included in the figure are 15 different cancer types showing ST6GAL1 amplification. Original data are available from the TCGA website: https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga This figure is available in black and white in print and in colour at Glycobiology online.
Fig. 3
Fig. 3
Promoters used to transcribe ST6GAL1 and their associated mRNA isoforms. Schematic representation of the genomic organization of ST6GAL1 and the three major ST6GAL1 transcripts. The three ST6GAL1 mRNA isoforms share exons I–VI. The shaded region denotes the coding sequence, which begins in Exon II and spans through part of Exon VI. The P3-driven ST6GAL1 isoform (“YZ form”) includes the untranslated exons Y and Z, whereas the P2-driven isoform (“X form”) includes the untranslated X exon. The P1-driven isoform, referred to as the “H form”, has a short sequence (solid) directly upstream of exon I. This figure was adapted from a manuscript by Dall'Olio et al. (2004). This figure is available in black and white in print and in colour at Glycobiology online.
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