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Letter

Altered adenosine-to-inosine RNA editing in human cancer

¹ Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel; ² Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; ³ Compugen Ltd., Tel Aviv 69512, Israel; ⁴ Department of Neurosurgery, Brain Tumor Center, University of Texas M.D. Anderson Cancer Center, Houston 77030, Texas, USA; ⁵ Department of Neurosurgery, Sourasky Medical Center, Tel Aviv 64239, Israel; ⁶ Department of Pediatric Neurosurgery, Dana Children’s Hospital, Sourasky Medical Center, Tel Aviv 64239, Israel; ⁷ Department of Internal Medicine, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel; ⁸ Pulmonary Institute, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel; ⁹ Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202, USA; ¹⁰ Neuro-Oncology Branch, NCI/NINDS, NIH, Bethesda 20892, Maryland, USA; ¹¹ School of Physics and Astronomy, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University 69978 Israel

Adenosine-to-inosine (A-to-I) RNA editing was recently shown to be abundant in the human transcriptome, affecting thousands of genes. Employing a bioinformatic approach, we identified significant global hypoediting of Alu repetitive elements in brain, prostate, lung, kidney, and testis tumors. Experimental validation confirmed this finding, showing significantly reduced editing in Alu sequences within MED13 transcripts in brain tissues. Looking at editing of specific recoding and noncoding sites, including in cancer-related genes, a more complex picture emerged, with a gene-specific editing pattern in tumors vs. normal tissues. Additionally, we found reduced RNA levels of all three editing mediating enzymes, ADAR, ADARB1, and ADARB2, in brain tumors. The reduction of ADARB2 correlated with the grade of malignancy of glioblastoma multiforme, the most aggressive of brain tumors, displaying a 99% decrease in ADARB2 RNA levels. Consistently, overexpression of ADAR and ADARB1 in the U87 glioblastoma multiforme cell line resulted in decreased proliferation rate, suggesting that reduced A-to-I editing in brain tumors is involved in the pathogenesis of cancer. Altered epigenetic control was recently shown to play a central role in oncogenesis. We suggest that A-to-I RNA editing may serve as an additional epigenetic mechanism relevant to cancer development and progression.

¹³ Corresponding author.

E-mail gidi.rechavi{at}sheba.health.gov.il; fax 972-3-5302377.

[Supplemental material is available online at www.genome.org.]

Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.6493107

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