Misunderstood gene thwarts tumors

A long non-coding RNA (lncRNA) called NBR2, once considered to be a “junk” gene, may very well play a significant role in tumor development, according to study findings published in the April issue of Nature Cell Biology.

“The NBR2 gene was originally identified as a gene that 'sits' right next to the breast cancer associated gene BRCA1 — perhaps the most well-known cancer gene to the general public,” said Boyi Gan, Ph.D., assistant professor of Experimental Radiation Oncology. “Given this, it was initially postulated that NBR2 may also play a role in cancers. However, later it became clear that NBR2 does not seem to encode a protein, and it was proposed that it was simply a ‘junk’ gene.”

Since then, Gan said, NBR2’s potential function in tumor biology has remained unknown. Until now.

Gan’s team identified NBR2 as an lncRNA induced by energy stress and showed that the gene functions to inhibit tumor development.

“It does this, in part, through its regulation of AMPK activation,” said Gan. "AMPK is the energy sensor in our cells, and it monitors how ATP, the molecular unit of currency of energy transfer in our body, is utilized. When this sensor goes awry, it leads to different diseases, including cancer. So AMPK must be carefully controlled in our normal cells. Our study found that NBR2 is one critical element to control this energy-sensing machinery. Unfortunately, cancer cells find different ways to hijack this machinery, partly by tuning down the level of NBR2, which facilitates tumor formation.

“This is an exciting story that links lncRNAs, genes that are often described as the ‘dark matter’ in our genome, to energy sensors in our cells. It has wide implications in human diseases,” said Gan. “AMPK is a kinase, one type of enzyme that we can design drugs to either activate or inhibit. In fact, there has been great interest in targeting AMPK through pharmacological means to treat human diseases. Understanding how a RNA molecule can modulate the enzyme activity of AMPK may facilitate such drug discovery.”

The most popular model proposed for lncRNA function is one whereby lncRNAs regulate gene expression through recruiting other chromatin-modification complexes or transcription factors to specific loci.

“This raises the possibility that NBR2 may regulate the transcription of BRCA1,” he said. “However, our current data does not support such a hypothesis.”

Gan added that it is important to note that while it was initially proposed that lncRNAs mainly function to regulate neighboring gene transcription, other studies have shown that many lncRNAs do not exert such a function.

“Whether NBR2 regulates any other gene transcription awaits further investigation,” said Gan.