Researchers at the University of Michigan Comprehensive Cancer Center uncovered a novel gene they named THOR while investigating previously unexplored regions of the human genome — or the human genome’s dark matter.
They characterized a long noncoding RNA (lncRNA) that is expressed in humans, mice and zebrafish. It’s unusual for this type of RNA to be conserved throughout species like this. The team’s thinking was that if the RNA plays a role in other animals and species besides humans, it must be important.
•THOR is a conserved lncRNA expressed in cancers and in normal testis
•THOR functions via a conserved interaction with IGF2BP1, stabilizing its targets
•Oncogenicity of THOR is corroborated in a zebrafish model
Large-scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. Here, we functionally characterize a novel ultraconserved lncRNA, THOR (ENSG00000226856), which exhibits expression exclusively in testis and a broad range of human cancers. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role. We discovered a conserved interaction of THOR with IGF2BP1 and show that THOR contributes to the mRNA stabilization activities of IGF2BP1. Notably, transgenic THOR knockout produced fertilization defects in zebrafish and also conferred a resistance to melanoma onset. Likewise, ectopic expression of human THOR in zebrafish accelerated the onset of melanoma. THOR represents a novel class of functionally important cancer/testis lncRNAs whose structure and function have undergone positive evolutionary selection.
“Genes that are evolutionarily conserved are likely important for biological processes. The fact that we found THOR to be a highly conserved lncRNA was exciting. We chose to focus on it with the thought that it has been selected by evolution for having important functions,” says Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Endowed Professor of Pathology at Michigan Medicine.
In fact, the researchers found this particular lncRNA plays a role in cancer development. And that knocking it out can halt the growth of tumors.
This is the first group to identify and characterize THOR, which stands for testis-associated highly conserved oncogenic long noncoding RNA. The researchers published their results in Cell.
It’s an early example of how this previously unexplored portion of the genome could lead to a potential new way of attacking cancer.
In addition to finding THOR expression in normal testis tissue, the researchers found it was highly expressed in some subsets of cancers, particularly lung cancer and melanoma. As they investigated THOR, they found its expression had a direct impact on cancer development. If they knocked down THOR in cell lines expressing it, tumor growth slowed. If they overexpressed THOR, cells grew faster. And when they eliminated THOR from normal cells, the cells continued to develop normally, suggesting it impacts only cancer cells.
“We’ve gone through a lot of lncRNAs to get to that. Most of the ones we test don’t have a clear function like this,” Chinnaiyan says.
Researchers also found that THOR impacted proteins called IGFBPs, which are thought to be involved in stabilizing RNAs. Knocking down THOR inhibited IGFBP activity.
“If we perturb THOR function, we disturb the ability to stabilize RNA. This inhibits cell proliferation,” Chinnaiyan says. Conversely, when researchers overexpressed THOR, cells grew faster.
Chinnaiyan suggests THOR could be a good target for drug development because blocking it does not impact normal cells. That would probably mean fewer toxic side effects. In future studies, the researchers will look at how to create a compound that binds with THOR in a complementary sequence designed to knock it down. This approach, known as antisense oligonucleotides, has been used successfully in other contexts.