Methylation is a process where a methyl group is added into critical points along human DNA. In cancer, many regions of the DNA are not methylated, leading to untimely gene expression, and unwanted cell reproduction. In some instances, genes that trigger cancer, known as oncogenes, spring into action.  DNA, or epigenetic, methylation affects the molecule’s function, including gene expression.

This ongoing chemical modification of a person’s DNA can help prevent cancer by maintaining a healthy level of gene expression, which in turn controls the extent of cell growth in the body.  To understand which factors decide which genetic expression in humans, scientists first identify how different molecules are supposed to act and, in turn, the elements that make their functions go awry.

Now, researchers from Case Western Reserve University have identified a novel long non-coding RNA (lncRNA), dubbed DACOR1, that slows the metabolism of cancer cells.  The team state that in part, their findings explain how cancer cells change their DNA methylation pattern, and this change is a major mechanism where normal cells become cancer cells.

Previous studies show that DNA methylation occurs through enzymes known as DNA methyltransferases (DNMTs), and there are only three of them in the human genome, DNMT1, DNMT3A and DNMT3B. DNMT1 is the most important one because of its activity in all cell types, so investigators focused on how a subset of lncRNAs might interact with DNMT1.  Therefore, the team’s hypothesis was that a subset of lncRNAs interacts with DNMT1 and that cancer cells alter the expression of these specific lncRNAs to change the location of where the DNMT1 enzyme triggers methylation along the DNA.

Earliers studies from the group found that specific lncRNAs regulate DNA methylation in specific human genes. The team also sought clues on how lncRNAs affect normal tissue versus cancerous tissue and characterized one particular lncRNA, DACOR1, which is present in healthy colon tissue and missing from colon cancer tissue.

In the current study the lab first isolated 148 lncRNAs from 8,300 known lncRNAs. These 148 lncRNAs are associated with DNMT1 in colon cells.  The lab then obtained normal and cancerous colon tissue from public datasets and compared how DACOR1 acted within each. Results show that DACOR1 is active in normal colon tissue and repressed in colon cancer tissue. The team also validated these findings in 21 colon cancer cell lines and observed that DACOR1 is suppressed in colon cancer.

The researchers then investigated whether returning DACOR1, and therefore, DNA methylation, to colon cancer cells would slow their growth. Data findings showed that in two colon cancer cell lines, the DNA methylation pattern changed when the lncRNA DACOR1 was injected into the cells. Additionally, investigators placed DACOR1 into cancer cells to track where this specific lncRNA went. It was shown that DACOR1 returned to those cancer-suppressing regions of the DNA where it had been missing in the cancer cells.

The team surmise that their experiments show that DNMT1-associated lncRNAs are regulating DNA methylation and subsequent gene expression, which controls cell growth.  For the future the researchers’ next challenge is to determine how to deliver DACOR1 to tumours where it may be able to slow, or even stop, the spread of malignant cells.

Source: Case Western Reserve University School of Medicine