Exercising restraint to stall tumor growth

The location of GalNAc-T enzymes (red) and the endoplasmic reticulum (ER; green) in normal cells (top). When the signaling protein ERK8 is inhibited, GalNAc-Ts move from the Golgi to the ER (yellow staining; bottom). Credit: Reproduced from Ref. 1 and licensed under CC BY 3.0  © 2014 J. Chia et al.

Many proteins undergo an assembly line-style process of glycosylation as they travel from a cellular structure called the endoplasmic reticulum (ER) to the Golgi apparatus and on through its various compartments, after which they are released. Disruptions in this process can contribute to a variety of diseases. Now researchers from A*STAR have identified a regulatory mechanism that prevents the production of glycosylated proteins that potentially promote cancerous growth1.

The process—executed by various enzymes in a stepwise fashion—attaches complex sugar molecules onto proteins, which can fundamentally alter the destination and function of these proteins in the cell. Many tumors produce proteins that are known as 'Tn antigens': these proteins have been decorated with a single sugar molecule by enzymes from the N-Acetylgalactosaminyltransferase (GalNAc-T) family.

GalNAc-T enzymes normally reside within the Golgi, but Frederic Bard and colleagues at the A*STAR Institute of Molecular and Cell Biology in Singapore previously showed that these enzymes relocate to the ER in certain tumors2. Here they target resident proteins for modification and thus contribute to Tn production.

To better understand why this happens, Bard's team screened more than 900 that affect Tn levels. Remarkably, their experiments uncovered a dozen different proteins that appear to ensure that GalNAc-T enzymes are retained within the Golgi instead of being delivered to the ER. "We were surprised by the number of regulators that we could identify," says Bard. One of these, a signaling protein called extracellular signal regulated kinase 8 (ERK8), appeared to be particularly important for restricting Tn accumulation to the Golgi.

When the researchers inhibited production of ERK8, they observed a clear redistribution of GalNAc-Ts from the Golgi to the ER, indicating that this protein normally puts the brakes on such 'backward' traffic (see image). "After knocking down ERK8, the relocation pathway responds like a compressed spring that has just been released," says Bard. The subsequent production of Tn antigens stimulates the active cell migration observed in aggressive cancers, and ERK8 similarly appears to act as a critical check against this behavior in cultured cancer cells.

The researchers also noted unusually low ERK8 levels in tumor tissue taken from breast and . Bard's team is now working with animal models to determine the importance of this as a safeguard against cancerous growth. "We are building a mouse model where we can experimentally remove ERK8 and observe the effects in healthy and cancer tissues," says Bard. "We predict that loss of ERK8 will promote tumor invasiveness."

More information: 1. Chia, J., Tham, K. M., Gill, D. J., Bard-Chapeau, E. A. & Bard, F. A. ERK8 is a negative regulator of O-GalNAc glycosylation and cell migration. eLife 3, e01828 (2014). dx.doi.org/10.7554/eLife.01828

2. Gill, D. J., Tham, K. M., Chia, J., Wang, S. C., Steentoft, C. et al. Initiation of GalNAc-type O-glycosylation in the endoplasmic reticulum promotes cancer cell invasiveness. Proceedings of the National Academy of Sciences USA 110, E3152–E3161 (2013). dx.doi.org/10.1073/pnas.1305269110

Related Stories

New technology offers insight into cholesterol

date Aug 14, 2014

With new advanced techniques developed by the Copenhagen Center for Glycomics at the University of Copenhagen it is possible to study cells in greater detail than ever before. The findings have just been ...

Recommended for you

Spicy treatment the answer to aggressive cancer?

date Jul 03, 2015

It has been treasured by food lovers for thousands of years for its rich golden colour, peppery flavour and mustardy aroma…and now turmeric may also have a role in fighting cancer.

Cancer survivors who smoke perceive less risk from tobacco

date Jul 02, 2015

Cancer survivors who smoke report fewer negative opinions about smoking, have more barriers to quitting, and are around other smokers more often than survivors who had quit before or after their diagnosis, according to a ...

Melanoma mutation rewires cell metabolism

date Jul 02, 2015

A mutation found in most melanomas rewires cancer cells' metabolism, making them dependent on a ketogenesis enzyme, researchers at Winship Cancer Institute of Emory University have discovered.

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.