Abstract 4324: Systematic characterization of A-to-I RNA editing in cancer development

Abstract

Abstract Adenosine (A) to inosine (I) RNA editing, mediated by ADAR enzymes, is a well-established RNA modification mechanism. Recent studies show that A-to-I RNA editing introduces a large number of nucleotide changes in both coding and noncoding regions in cancer transcriptomes. First, to elucidate the contribution of RNA editing to proteomic diversity in human cancer, we performed an integrated analysis of The Cancer Genome Atlas (TCGA) genomic data and proteomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). We detected a considerable contribution of RNA editing in terms of amino acids changes induced per tumor sample in breast cancer. We validated some of these editing events at both RNA and protein levels, and further experimentally demonstrated the functional effects of some edited protein (e.g., increased proliferation, migration, and invasion of cancer cells in vitro). Second, we systematically characterized the miRNA editing hotspots across 20 cancer types from TCGA miRNA sequencing data and independently validated the vast majority of them by perturbation experiments in several cancer cell lines. These miRNA editing events show extensive correlations with key clinical variables and other molecular drivers. Focusing on the RNA editing hotspot in miR-200b, a key tumor metastasis suppressor, we found that the miR-200b editing level correlates with patient prognosis opposite to that pattern for the wild-type miR-200b expression. We further experimentally showed that in contrast to wild-type miRNA, the edited miR-200b can promote cell invasion and migration through its impaired ability to inhibit ZEB1/ZEB2 and acquired concomitant ability to repress new targets including LIFR, a well-characterized metastasis suppressor. Our results highlight the contribution of A-to-I RNA editing in cancer development and suggest its translational potential as both biomarkers and therapeutic targets. Citation Format: Han Liang. Systematic characterization of A-to-I RNA editing in cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4324.