Elephants have evolved a way to make LIF6 (a non-functioning, or dead, gene in mammals) come back to life, and it's what makes the largest living land mammals nearly immune to cancer. 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. The research publishes August 14 in the journal Cell Reports.
"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," says senior author Vincent Lynch (@DevoEvoMed), a geneticist and evolutionary biologist at the University of Chicago. "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."
All of the elephant's close relatives, such as the manatee and groundhog-sized hyrax, are much smaller than it is, which allowed the researchers to isolate elephant-specific genetic variations and focus on which ones could be associated with cancer suppression. First, they introduced cancer-causing DNA damage to cells from both the elephant and its smaller relatives to see whether the elephant cells responded differently to the threat of cancer.
"The elephant cells just died; they were entirely intolerant of DNA damage in a way their relatives' cells were not," Lynch says. "Because the elephant cells died as soon as their DNA was damaged, there was no risk of them ever becoming cancerous."
Next, the scientists had to find the genetic mechanism responsible for this behavior. Because part of his lab studies the role of LIF in pregnancy and because one of the proteins the gene produces helps in tumor suppression, Lynch was excited to see it copied so many times in the elephant genome and immediately suspected its role.
When the researchers blocked LIF6 expression, the elephant cells started responding like non-elephant cells, tolerating DNA damage and becoming cancerous over time. And when they overexpressed LIF6 in animals that don't normally have it, like mice, all of their cells with DNA damage underwent apoptosis. This means that the gene LIF6 is responsible for the heightened sensitivity that elephant cells have for cancer-inducing DNA damage.
"First some stress is introduced, like cancer-inducing DNA damage, that turns on the tumor-suppressor p53," says Lynch. "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."
But elephants aren't the only animals that have evolved cancer resistance. "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 says.
After this, Lynch and his colleagues want to apply the elephants' strategy for cancer resistance to human cancer biology. "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," says Lynch.
This research was funded by the Else Kröner-Fresenius Stiftung, Eva Luise Köhler 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.
Cell Reports, Vazquez et al.: "A zombie LIF gene in elephants is up-regulated by TP53 to induce apoptosis in response to DNA damage" https://www.cell.com/cell-reports/fulltext/S2211-1247(18)31145-8
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