A Novel Protein That Promotes Cancer Progression Revealed

Cancer occurs when the genetic code of normal cells is changed, causing excessive growth. Researchers at the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) have discovered a protein that drives the growth of esophageal or liver cancer by altering the genetic code in a novel way.

This protein called death associated protein 3 (DAP3) inhibits a process called adenosine-inosine (A-to-I) RNA editing, which usually corrects the genetic code to ensure the correct expression of genes. By inhibiting RNA editing, DAP3 becomes an oncogene— a gene that has the potential to cause cancer. The findings provide potential for the development of new drugs for cancer treatment against DAP3.

The study, led by Polly Chen, lead researcher and assistant professor at CSI in Singapore, was recently published in the scientific journal Science Advances.

RNA is the most important class of molecules in cells. They not only convert genetic information stored in DNA into proteins, but also play important regulatory roles in various biological processes. RNA editing is a process in which RNA produced by DNA transcription is altered, resulting in altered proteins. In humans, the most common type of RNA editing is A-to-I editing, mediated by ADAR proteins (ADAR1 and ADAR2). Over the past decade, many studies have reported that the accumulation of deleterious changes in A-to-IRNA editing can trigger cells to develop cancer. However, current knowledge on how the A-to-I RNA editing process is regulated in cancer remains limited.

Therefore, the CSI Singapore research team carried out a study to understand how DAP3, an interacting protein of A-to-I RNA-editing catalytic enzymes (ADAR1 and ADAR2), regulates the process in cancer cells.

The team demonstrated that DAP3 can disrupt the binding of ADAR2 protein to target RNA, thereby inhibiting the editing of A-to-I RNA in cancer cells. This inhibition may be one of the pathways by which DAP3 promotes tumor development.

Their analysis also showed that DAP3 expression was elevated in 17 cancers. Further experiments showed that DAP3 acts as an oncogene in esophageal cancer and liver cancer cells. Interestingly, they also found that one of the editing targets inhibited by DAP3 was the PDZD7 gene, and found that altering the editing of PDZD7 generated new PDZD7 protein products that promoted DAP3-driven tumor growth.

Collectively, these observations reveal the complexity of the A-to-I RNA editing process in cancer cells and suggest that DAP3 may be a promising target for future cancer drug development.

"With this new knowledge, we can now study how to intervene in the interaction between DAP3 and ADAR proteins to intervene in RNA-editing-mediated cancer promotion processes in cells," said Professor Chen, a research leader Asst.