Protein distortion may be linked to skin cancer

Researchers at Rockefeller University have shown that a shift in translation, the process by which cells produce proteins from RNA, may promote skin cancer.

In order to function, cells need to turn instructions encoded in their DNA into protein. They do so in two major steps:

• DNA is transcribed into a molecule called messenger RNA;
• messenger RNA is then translated into protein.

Within the pre-malignant cells, the researchers found decreases in regular protein production as well as an uptick in tumor-promoting proteins. Certain cancerous tumors are known to contain an unusual ratio of protein to messenger RNA, however, which suggests translation is altered in cancer. [1]

“A cell’s identity depends on the levels of proteins it produces, and these can be altered by changes in the way proteins are translated from genetic instructions,” said senior author Elaine Fuchs, head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development.

Using mice, the team explored changes in translation that occur as the animals develop squamous cell carcinoma, a common skin cancer. The researchers captured messenger RNA as it was being translated within skin stem cells in mice. These molecules were collected from both normal skin stem cells and those primed to become malignant.

Within the pre-malignant cells, the researchers found decreases in regular protein production as well as an uptick in tumor-promoting proteins. This shift was traced back to a change in the proteins that kick off the process of translation. In regular skin cells, eIF2 has this job; in the soon-to-be cancerous cells, eIF2 was found to be inactivated, and eIF2A had taken over.

The researchers looked for evidence that eIF2A has a similar role in humans. By searching the publicly available Cancer Genome Atlas, which contains genetic data from 11,000 patients, they found extra copies of the gene encoding eIF2A in 29 percent of patients with squamous cell carcinomas in the lungs, and in 15 percent of those with tumors in the head or neck.

Moreover, patients in whose cells the gene was more active had a poorer prognosis, surviving and remaining disease-free for less time compared to those with normal eIF2A activity.

“By looking for molecular inhibitors that can turn off eIF2A — and, as a result, the translation of cancer-associated proteins — we suspect it may be possible to stop the formation of new tumors,” said Ataman Sendoel, a postdoc in the Fuchs lab and first author on the study. “For instance, one could envision using such a treatment after tumor surgery to inhibit any tumor-initiating cells that remain.”

The research, which identifies a potential avenue for future cancer treatments, was described in Nature. [2]