‘Zombie’ Gene Roots Out Cancer in Elephants

(CN) – Elephants possess a “zombie” gene that makes them nearly immune to cancer, according to research published Tuesday in the journal Cell Reports – a finding that offers hope for applications in human cancer biology.

Scientists aptly named gene LIF6 in the largest living land mammal the “zombie gene,” given the elephant’s ability to make a nonfunctioning “dead” gene come back to life. In response to DNA damage, such as that caused by mistakes during cell division or by ultraviolet rays, the elephant version of the tumor-suppressing protein p53 prompts “zombie” LIF6 to efficiently kill cells poised to become cancerous.

“Elephants get cancer far less than we’d expect based on their size, so we want to understand the genetic basis for this cancer resistance,” senior author Vincent Lynch, a geneticist and evolutionary biologist at the University of Chicago, said. “We found that elephants and their relatives have many non-functioning copies of the LIF gene, but that elephants themselves evolved a way to turn one of these copies, LIF6, back on.”

Researchers were able to isolate elephant-specific genetic variations that suppressed cancer by comparing their LIF genes with those of close but smaller relatives, the manatee and groundhog-sized hyrax. Fossil records and molecular dating suggest that the cancer-fighting LIF6 gene evolved after the larger species branched off from its relatives and while elephants were evolving to their larger bodies.

To begin their study, scientists introduced cancer-causing DNA damage to cells from both the elephant and its smaller relatives. “The elephant cells just died; they were entirely intolerant of DNA damage in a way their relatives’ cells were not,” Lynch stated. “Because the elephant cells died as soon as their DNA was damaged, there was no risk of them ever becoming cancerous.”

Next, the scientists searched for the genetic mechanism responsible for this behavior and found it by looking at tumor-suppressing proteins produced by LIF genes during pregnancy.

When the researchers blocked LIF6 expression, the elephant cells started responding like non-elephant cells, tolerating DNA damage and becoming cancerous over time. Doing the reverse, overexpressing LIF6 in animals that don’t normally have it like mice, researchers found all of the abnormal cells died off, proving that gene LIF6 is responsible for elephant cells successfully fending off cancer.

“First some stress is introduced, like cancer-inducing DNA damage, that turns on the tumor-suppressor p53,” Lynch explained. “This in turn activates the gene LIF6 that can then go to the mitochondria, cause its insides to leak out, and trigger apoptosis, or cell death.”

Elephants aren’t the only animals that have evolved cancer resistance, but they are the only ones thus far reawakening defunct LIF genes to do it, according to the study.

“Species like whales, bats, and naked mole rats don’t have these zombie LIF genes, which means that they have evolved cancer resistance using a different strategy and that there are many ways animals can combat cancer,” Lynch said.

Lynch and his colleagues see human implications in the elephant’s cancer resistance strategy. “Maybe we can find ways of developing drugs that mimic the behaviors of the elephant’s LIF6 or of getting cancerous cells to turn on their existing zombie copies of the LIF gene,” Lynch added.

The Else Kroner-Fresenius Stiftung, Eva Luise Kohler Research Award for Rare Diseases, Deutsche Forschungsgemeinschaf, the German ministry for education and technology, the German Center for Lung Research, Hannover Medical School, and the National Institutes of Health funded the study.

Cell Reports is a weekly open-access journal that features reports, articles, and resources that provide new biological insights and examples of cutting-edge research.

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