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Targeting Cellular Stress-Controlling Gene Suppresses Brain Cancer Growth in Mice

An image of fluorescent cells visualized using a microscope.
Researchers discovered the mechanism of interaction among TUG1 (red), R-loops (green), and another protein (blue) in cancer cells, which provides a key to therapeutic applications. Credit: Yutaka Kondo, Nagoya University
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Researchers have identified a gene that links cancer cells’ ability to cope with DNA replication stress to cancer growth. The study, which highlights a potential strategy to combat aggressive brain cancers like glioblastoma by targeting this gene, is published in Nature Communications.

Striking a delicate balance

When cells become cancerous, they create an environment around them that supports them and aids their growth. They can even use routine cellular processes, like replication, as tools to give them a competitive edge.

Cells replicate their DNA just before they divide to ensure each new cell is supplied with a complete copy of the genome. During replication, double-stranded DNA molecules are unraveled into single strands. Each strand serves as a template to be copied into a new strand of DNA. These bind to RNA that stabilizes the unwound single strands, forming a three-stranded structure called an R-loop.

Unfortunately, cancer cells can manipulate this process to favor tumor growth. They can induce replication stress, promoting the breakage of double-stranded DNA into single strands and creating genomic instability. However, cancer cells must strike a delicate balance, as the presence of R-loops can also stimulate cell death.

To avoid cell death and regulate the genome, cancer cells use molecules called long non-coding RNAs (lncRNAs) to remove unwanted R-loops. In the current study, researchers from Nagoya University discovered how one lncRNA – taurine upregulated gene 1 (TUG1) – prevents R-loop formation in cancer cells and identified how it represents a potential therapeutic target.

TUG1 controls replication stress

The researchers, led by Yutaka Kondo and Miho Suzuki, found that TUG1 works to suppress R-loop formation alongside two proteins – DHX9 and RPA32. The interaction between these three factors was found to be essential to prevent R-loops in DNA regions susceptible to damage and mutations.

Next, they discovered that replication stress leads to swift upregulation of TUG1. Additionally, they found significant DNA damage and cell death in cancer cells engineered to produce lower levels of TUG1.

“It was exciting to see the rapid increase in expression of TUG1 in response to replication stress,” explained Suzuki, an assistant professor at Nagoya University and lead author of the study. “Normally, it takes several hours or more for proteins to increase in response to stimuli, but RNA can be synthesized rapidly. That TUG1, an RNA molecule, increases immediately in response to replication stress indicates that it is necessary to respond quickly to critical situations.”

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“These findings have the potential to be translated into therapeutic applications, as TUG1 is highly expressed in glioblastoma,” Suzuki continued. “In this study, we successfully developed a therapeutic drug named TUG1-DDS, which selectively targets TUG1. It significantly suppressed tumor growth and improved survival, especially when administered in combination with the standard treatment of temozolomide. Therefore, it is a potentially effective therapeutic agent for treating glioblastoma.”

Kondo also described how these findings offer hope for the development of treatment for other cancers that also produce TUG1: “TUG1 inhibitors have also been found to be effective in other types of cancer, such as pancreatic cancer and ovarian cancer. Therefore, our novel treatment, TUG1-DDS, could also be effective in other cancer types with expression of TUG1.”

Reference: Suzuki MM, Iijima K, Ogami K, et al. TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation. Nat Commun. 2023;14(1):4521. doi: 10.1038/s41467-023-40243-8

This article is a rework of a press release issued by [name of institute]. Material has been edited for length and content.