Researchers have recognized an enzyme that is absent in wholesome colon tissue however ample in colon cancer cells, in line with a report within the Jan. 26 situation of the Journal of Biological Chemistry. The enzyme seems to drive the conversion of regular colon tissue into cancer by attaching sugar molecules, or glycans, to sure proteins within the cell. Understanding the position that sugar-modified (glycosylated) proteins play in wholesome and cancerous cells is an rising space of cancer biology that might result in new therapies.
Hans Wandall’s staff on the University of Copenhagen studied a gaggle of 20 enzymes that provoke step one in a specific type of glycan modification, referred to as GalNAc-type O-glycosylation, discovered on numerous proteins. These enzymes, referred to as GalNAc transferases (GalNAc -Ts) are variously discovered in several quantities in several tissues, however their features are poorly understood.
Wandall’s group, led by then-graduate scholar Kirstine Lavrsen, discovered that one of many GalNAc-Ts, referred to as GalNAc-T6, was absent in wholesome colon tissue however ample in colon cancer cells. The group used CRISPR/Cas engineering of a colon cancer cell line with and with out GalNAc-T6 to know which proteins the enzyme helped connect sugars to, and what impact this had on the cells.
“When we look at the 3D growth of a cancer cell line that has GalNAc-T6, it can form tubular structures with formation of something that looks like colon cancer tissue,” Wandall stated. “When we take out GalNAc-T6, then suddenly the tissue formation changes to look more like the crypt structures that you would find in a healthy colon.”
Using mass spectrometry, the staff categorized the proteins that GalNAc-T6 acted on in these cells. “Our data suggest [that] this specific enzyme seems to affect a subset of proteins that could be involved in cell-cell adhesion,” Wandall stated. In different phrases, the glycan modifications modified the patterns through which cells caught collectively, main the cells to develop as one thing that appeared extra like a tumor than a wholesome tissue.
The subsequent step, then, is to know exactly why including sugars to the precise protein websites modified by GalNAc-T6 leads colon cells to develop abnormally. Glycan modifications can have an effect on protein perform in myriad methods. For instance, they will make proteins that are often cleaved into two unable to be cleaved, or forestall two proteins from binding to one another.
Wandall hopes that understanding glycosylation in cancer cells will result in higher early diagnostic instruments, medicine or immunotherapies. “Glycans add an additional context layer that could help us create more specific interventions,” Wandall says.
“Glycans look so totally different in cancer in comparison with regular tissue, and it is a actually understudied subject,” Lavrsen stated. “There are a lot of things to be discovered.”
Kirstine Lavrsen et al, De novoexpression of human polypeptideN-acetylgalactosaminyltransferase 6 (GalNAc-T6) in colon adenocarcinoma inhibits the differentiation of colonic epithelium, Journal of Biological Chemistry (2017). DOI: 10.1074/jbc.M117.812826