Lack of RNA ‘editing’ leads to melanoma growth and metastasis

MD Anderson Study Finds Regulated ADAR1 gene key contributor

MD Anderson News Release 02/13/2015

The importance of RNA editing in melanoma has been demonstrated by scientists at The University of Texas MD Anderson Cancer Center.  The study revealed that a lack of RNA editing, a process by which information inside RNA molecules is transformed, leads to tumor growth and progression through manipulation of proteins.

Menashe Bar-Eli, Ph.D.

Study lead Menashe Bar-Eli, Ph.D., professor of Cancer Biology, reported a previously unknown target for CREB (cAMP response element-binding protein), a transcription factor that regulates other transcription factors involved in melanoma development. Transcription factors are proteins that turn genetic instructions on and off.

“We found that CREB regulates ADAR1, an enzyme involved in RNA editing,” said Bar-Eli, whose study findings appear in this month’s issue of Nature Cell Biology. “CREB negatively regulated ADAR1, promoting melanoma tumor growth and metastasis.”

“When we discovered that CREB negatively regulated ADAR1, we looked further into how the loss of ADAR1 expression contributes to the cancer spread.”

Bar-Eli’s team evaluated the RNA editing functioning of ADAR1 in microRNAs (miRNAs). MicroRNAs are small, non-coding molecules that have been linked to several types of cancer. Bar-Eli identified adenosine-to-inosine RNA editing in three miRNAs. RNA editing occurs only in the non-metastatic (ADAR1-positive), but not in the metastatic melanoma cells (ADAR1-negative).

Manipulation of the miRNAs by silencing the naturally occurring or wild-type version of a miRNA and overexpressing an “edited” miRNA confirmed the significance of RNA editing in tumor growth and metastasis.

“We found that increased wild-type miRNA led to increased tumor growth and cancer spread,” said Bar-Eli. “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.”

The team’s investigation involved study of cell lines, mice and data from The Cancer Genome Atlas (TCGA). The TCGA is a research program supported by the National Cancer Institute and National Human Genome Research Institute within the National Institutes of Health that is looking at genomic changes in more than 20 different types of cancer.

Bar-Eli’s study was funded by the National Institutes of Health (p50 CA093459), an MD Anderson Cancer Center grant, and MD Anderson’s Sister Institute Network Fund.

MD Anderson team members included Einav Shoshan, Ph.D., Aaron Mobley, Ph.D., Russell Braeuer, Ph.D., Takafumi Kamiya, Ph.D., Li Huang, Mayra Vasquez, Ho Jeong Lee, Ph.D., Sun Jin Kim, M.D., Ph.D., Anil Sood, Ph.D., and Isaiah Fidler, Ph.D., all of the Cancer Biology department; Cristina Ivan, Gynecologic Oncology; George Calin, M.D., Ph.D., Experimental Therapeutics; Patrick Hwu, M.D., Melanoma Medical Oncology; and Jeffrey Gershenwald, M.D., Surgical Oncology. Participating institutions included The University of Texas Health Science Center at Houston, Sheba Medical Center, Tel Aviv University, Israel, and the Michael Smith Cancer Agency, Vancouver, British Columbia.