© Callista Images/Getty

Relocated enzymes make cancer more mobile

18 Apr 2018

Relocation of enzymes involved in protein modification makes it easier for cancer to spread

Relocation of N-acetylgalactosaminyltransferases from the Golgi apparatus to the endoplasmic reticulum makes cancer cells more invasive.

Relocation of N-acetylgalactosaminyltransferases from the Golgi apparatus to the endoplasmic reticulum makes cancer cells more invasive.

© Callista Images/Getty

Enzymes that are involved in protein modification are relocated in cancer cells, altering protein processing and helping cancer to spread, according to new work by A*STAR researchers. The mechanism, which was studied in liver cancer, reveals novel potential targets for cancer treatments.

During their production, many cell surface proteins undergo glycosylation — a process which involves attachment of sugar molecules, called glycans, to specific sites on proteins. This normally takes place in the Golgi apparatus, after the protein has been transferred from the endoplasmic reticulum (ER) where it was made. “Glycosylation is a poorly understood process,” explains Frederic Bard from the A*STAR Institute of Molecular and Cell Biology, who led the new study, “yet it is involved in virtually every aspect of human biology and it has long been known that glycosylation is altered in cancer.”

In liver cancers, some of the enzymes involved in glycosylation have been shifted from the Golgi to the ER. Altered glycosylation in cancer is associated with more invasive — and therefore more deadly, tumors — but the underlying mechanisms are unclear. Bard and colleagues investigated these mechanisms in liver cancer, focusing on the initial step of glycosylation in which the glycan N-acetylgalactosamine (GalNAc) is attached to proteins by enzymes called N-acetylgalactosaminyltransferases (GALNTs). The researchers had previously proposed that relocation of GALNTs from the Golgi apparatus to the ER affects glycosylation in cancer, and was investigating whether there was further evidence to support this case.

The team first demonstrated that GALNTs are active at the ER in liver tumor cells from mice and humans, rather than being active at the Golgi apparatus as they are in healthy cells. Furthermore, genetic targeting of GALNT1 to the ER in mice with liver cancer reduced survival from 23 weeks to just 10 weeks.

Frederic Bard (fifth from the right) and his team.

Frederic Bard (fifth from the right) and his team.

© 2018 A*STAR Institute of Molecular and Cell Biology

Further experiments in the mice and cultured cells revealed that relocation of GALNT1 to the ER caused increased glycosylation of the protein matrix metalloproteinase 14 (MMP14). This in turn led to breakdown of the extracellular matrix that keeps cells in place, making it easier for cancer cells to break away from the primary tumor and invade other tissues. “Glycosylation activates the mechanisms by which cancers destroy normal tissue, making space for their own growth,” explains Bard.

The researchers say their findings suggest that GALNTs, and the mechanisms that control their relocation to the ER, are potential therapeutic targets for cancer treatments. Identification of similar mechanisms could reveal further potential targets. “While we focused on MMP14, we have preliminary evidence that many cell surface proteins are regulated by hyperglycosylation,” concludes Bard, “We are currently exploring how these other proteins contribute to tumor development.”

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology. For more information about the team’s research, please visit Frederic Bard’s webpage.

Want to stay up-to-date with A*STAR’s breakthroughs? Follow us on Twitter and LinkedIn!


Nguyen, A. T., Chia, J., Ros, M., Hui, K.M., Saltel, F. et al. Organelle specific O-glycosylation drives MMP14 activation, tumor growth, and metastasis. Cancer Cell 32, 639–653.e6 (2017).| Article

This article was made for A*STAR Research by Nature Research Custom Media, part of Springer Nature