Decreased RNA-Editing Promotes Melanoma Progression

Source: Melanoma News Today, February 2015

A new study entitled “Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis” showed how lack of RNA-editing, a key cellular process whereby RNA nucleotides are modified, contributes to tumor growth and cancer progression in melanoma by increasing the expression of an oncogenic miRNA. The study was published in the February edition of the journal Nature Cell Biology.

In this study, a research team at The University of Texas MD Anderson Cancer Center used melanoma cancer cell lines in mice to understand how a previously identified transcription factor, cyclic AMP-responsive element-binding protein (CREB) promotes melanoma progression. The authors inhibited the expression of CREB in highly metastatic melanoma cells and discovered that CREB down-regulation leads to the increased expression of a particular enzyme, ADAR1. This enzyme is part of a family of enzymes – adenosine deaminases acting on RNA (ADAR) – that perform RNA editing, more specifically adenosine-to-inosine (A-to-I) editing. Notably, in a previous collaborative study they found that ADAR1 is commonly down-regulated in metastatic melanomas and that ADAR1 regulated the expression of more than 100 microRNAs (miRNAs) involved in cancer. Additionally, the researchers already knew that both ADAR1 expression and activity was inversely correlated with melanoma progression.

The researchers hypothesized that decreased RNA-editing activity of ADAR1 in microRNAs could promote melanoma progression. In agreement with their rationale, the team discovered that A-to-I RNA-editing occurred in three miRNAs in cells with low metastatic potential, but no editing was found in highly metastatic cell lines. The team focused on a specific microRNA – miR-455-5p – since it exhibited two A-to-I RNA-editing sites. They observed that while wild-type miR-455-5p promoted in vivo melanoma growth and metastasis through inhibition of the tumor suppressor gene CPEB1, the edited form inhibited both phenotypes.

These findings revealed a previously unrecognized link between CREB and ADAR1 in metastatic melanoma cell lines and tumors, and for the first time showed a role for RNA editing in melanoma progression.

As noted by study leading author, Menashe Bar-Eli, Ph.D., professor of Cancer Biology in a press release: “We found that increased wild-type miRNA led to increased tumor growth and cancer spread. In contrast, overexpression of the edited miRNA led to decreased tumor growth and metastasis. The biological functions of edited mi RNAs are different from unedited forms, as they recognize a different set of genes. These results demonstrate a previously unrecognized role for RNA editing in melanoma progression.”