A new study by the University of Colorado Boulder has been published in the journal Science Advances, showing that DNA sequences originating from ancient viral infections, which are normally silenced in healthy cells, can be “switches” to turn on nearby cancer genes.
Approximately 8% of the human genome consists of sequences called endogenous retroviruses (ERVs), produced by historic viral infections. The researchers found that silencing certain ERVs could be useful in cancer treatments.
Previous research established that ERVs can function as “switches” that turn on nearby genes for viruses, contributing enhancers to beneficial functions, such as the development of the placenta and immune responses to modern viruses such as SARS-CoV-2.
The researchers analyzed genomic data from 21 human cancer types from publicly available datasets to identify that LTR10 displays tumor-specific transcriptional activation in approximately 30% of cases. LTR10 is a line of ERV that slipped into the cells of human ancestors millions of years ago.
They used CRISPR-based epigenome editing technology to silence or knock out sequences with the LTR10, and switched off critical genes known as the promotion of cancer development. They removed the LTR10 “switch” from mouse tumor cells to help shrink tumors more effectively.
They also proved that using MAPK inhibitors in cancer treatment effectively silenced LTR10 activity in cancer cells. LTR10 seems to respond to switch-on genes in the MAP-kinase pathway, which plays a key role in regulating cellular processes, such as cell growth, migration, proliferation, differentiation, and survival.
The pathway is often unfavorably changed in many cancers by MAP-kinase inhibitors, which are used in cancer treatments to block uncontrolled cell division and prevent tumor growth in humans.
The advantage of CRISPR technology used in this study to silence ERV switches is it can adjust gene transcription through the epigenome, without editing the primary DNA sequence intact, a cause to increase the risk of more damage like making a cancer-causing mutation. This has also proven its ability for the potential use of this technology in clinical treatments.
In addition, this study also shows that ancient viruses could still play a role in other diseases when genomic defenses break down. Therefore, this will be a key area needed for future studies.
