The Gb3-synthase A4GALT is an epigenetically regulated driver of tumor invasiveness in gastrointestinal cancer

Sep 23, 2026

Uploaded by Connor

Tumor lipid metabolism influences cancer progression, with globotriaosylceramide (Gb3/CD77) being a key glycosphingolipid and receptor for Shiga toxins that is upregulated in multiple malignancies. The study investigates how Gb3 biosynthesis is regulated in human gastrointestinal tumors. It shows that the glycosyltransferase A4GALT and the degrading enzyme α-galactosidase A control Gb3 levels, and that epigenetic mechanisms govern A4GALT expression, shaping invasion-associated programs and prognostic signatures across cancer cohorts.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusions

Introduction

Hirsch et al. BMC Cancer (2026) 26:274 BMC Cancer [https://doi.org/10.1186/s12885-026-15600-7](https://doi.org/10.1186/s12885-026-15600-7) RESEARCH Open Access The Gb3-synthase A4GALT is an epigenetically regulated driver of tumor invasiveness in gastrointestinal cancer Noah-David Hirsch 1†, Markus Perl1,2†, Simon Holzinger2,3,4†, Christoph Barz 1,5, Stefan Enßle6,7, Widya Johannes1, Anja Conrad1, Jonas J. Unterholzner 1,8, Viktoria Obermeier9, Markus Tschurtschenthaler10,11,12, Ludger Johannes13,14 and Klaus-Peter Janssen1* Abstract Background Tumor lipid metabolism has emerged as a critical, yet underexplored, determinant of cancer progression with clinical and prognostic importance. A membrane lipid species of particular interest is globotriaosylceramide (Gb3/CD77), a glycosphingolipid that serves as cellular receptor for the bacterial Shiga toxins, and is upregulated in various malignancies. While preclinical studies have suggested a pro-tumorigenic role for Gb3, the regulatory drivers of its biosynthesis in human tumors have remained elusive. Methods The glycosyltransferase A4GALT, responsible for Gb3 biosynthesis, and the degrading enzyme α-galactosidase A (α-GLA) are two essential molecular determinants of Gb3 cell surface expression. Expression of these enzymes was analyzed on mRNA level in tissues from colorectal cancer, published datasets from gastric, pancreatic, esophageal and colorectal cancer (1213 patients) and in human cell lines. Pharmacological manipulation in vitro using the hypomethylating agent 5-Aza-2-deoxycytidine and histone deacetylase (HDAC) inhibitors induced A4GALT expression in DLD1 colon cancer cells and Gb3 biosynthesis. A4GALT deficiency was induced by CRISPR-Cas9 mutagenesis in human HCT116 colon cancer cells, and its putative effects tested for proliferation, cell migration and invasion. Results A4GALT deficiency in HCT116 cells confirmed its essential role for Gb3 biosynthesis, leading to resistance against Shiga toxin 1a, and to reduced cancer cell migration and invasion. Gene enrichment analyses revealed that high A4GALT and low α-GLA expression is associated with a distinct gene expression program in gastric, pancreatic and colorectal cancer, including increased signatures of epithelial–mesenchymal transition. A4GALT expression is regulated by chromatin accessibility and DNA methylation at a defined intronic enhancer. In accordance, pan-cancer analysis of TCGA datasets validated the A4GALT-high/α-GLA-low signature as a negative prognostic indicator across gastrointestinal tumor entities. †Noah-David Hirsch, Markus Perl and Simon Holzinger contributed equally to this work. *Correspondence: Klaus-Peter Janssen [klaus-peter.janssen@tum.de](klaus-peter.janssen@tum.de) Full list of author information is available at the end of the article © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/.)[.](http://creativecommons.org/licenses/by/4.0/.) Hirsch et al. BMC Cancer (2026) 26:274 Page 2 of 14 Conclusions Our study uncovers an epigenetically regulated lipid metabolic axis involving A4GALT and Gb3 that contributes to a

FAQs

What molecular pathway regulates Gb3 levels in gastrointestinal cancers?

The study identifies A4GALT as the Gb3 biosynthesis enzyme and α-GLA as the degrading enzyme that together determine Gb3 cell-surface expression.

How does A4GALT deficiency affect cancer cell behavior?

CRISPR-Cas9–induced A4GALT deficiency confirms Gb3 biosynthesis dependence, confers resistance to Shiga toxin 1a, and reduces migration and invasion in HCT116 cells.

Which epigenetic mechanisms control A4GALT expression?

A4GALT expression is regulated by chromatin accessibility and DNA methylation at a defined intronic enhancer, producing a characteristic A4GALT-high/α-GLA-low gene signature.

Sep 23, 2026

Uploaded by Connor