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The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers
Han, L.,Diao, L.,Yu, S.,Xu, X.,Li, J.,Zhang, R.,Yang, Y.,Werner, Henrica M.J.,Eterovic, A.,Yuan, Y.,Li, J.,Nair, N.,Minelli, R.,Tsang, Y.,Cheung, Lydia W.T.,Jeong, K.,Roszik, J.,Ju, Z.,Woodman, Scott Cell Press 2015 CANCER CELL Vol. No.
Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions. We experimentally demonstrated the effects of several cross-tumor nonsynonymous RNA editing events on cell viability and provide the evidence that RNA editing could selectively affect drug sensitivity. These results highlight RNA editing as an exciting theme for investigating cancer mechanisms, biomarkers, and treatments.
Sun, Chaoyang,Fang, Yong,Yin, Jun,Chen, Jian,Ju, Zhenlin,Zhang, Dong,Chen, Xiaohua,Vellano, Christopher P.,Jeong, Kang Jin,Ng, Patrick Kwok-Shing,Eterovic, Agda Karina B.,Bhola, Neil H.,Lu, Yiling,Wes American Association for the Advancement of Scienc 2017 Science translational medicine Vol.9 No.392
<P>Mutant <I>RAS</I> has remained recalcitrant to targeted therapy efforts. We demonstrate that combined treatment with poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors and mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple <I>RAS</I> mutant tumor models across tumor lineages where <I>RAS</I> mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of <I>BRCA1/2</I> and <I>p53</I> mutation status, suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in <I>RAS</I> mutant tumors is associated with (i) induction of BIM-mediated apoptosis, (ii) decrease in expression of components of the homologous recombination DNA repair pathway, (iii) decrease in homologous recombination DNA damage repair capacity, (iv) decrease in DNA damage checkpoint activity, (v) increase in PARP inhibitor–induced DNA damage, (vi) decrease in vascularity that could increase PARP inhibitor efficacy by inducing hypoxia, and (vii) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus, the ability of mutant <I>RAS</I> to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in <I>RAS</I> mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with <I>RAS</I> mutant tumors where there are few effective therapeutic options.</P>
Systematic characterization of A-to-I RNA editing hotspots in microRNAs across human cancers
Wang, Yumeng,Xu, Xiaoyan,Yu, Shuangxing,Jeong, Kang Jin,Zhou, Zhicheng,Han, Leng,Tsang, Yiu Huen,Li, Jun,Chen, Hu,Mangala, Lingegowda S.,Yuan, Yuan,Eterovic, A. Karina,Lu, Yiling,Sood, Anil K.,Scott, Cold Spring Harbor Laboratory Press 2017 Genome research Vol.27 No.7
<P>RNA editing, a widespread post-transcriptional mechanism, has emerged as a new player in cancer biology. Recent studies have reported key roles for individual miRNA editing events, but a comprehensive picture of miRNA editing in human cancers remains largely unexplored. Here, we systematically characterized the miRNA editing profiles of 8595 samples across 20 cancer types from miRNA sequencing data of The Cancer Genome Atlas and identified 19 adenosine-to-inosine (A-to-I) RNA editing hotspots. We independently validated 15 of them by perturbation experiments in several cancer cell lines. These miRNA editing events show extensive correlations with key clinical variables (e.g., tumor subtype, disease stage, and patient survival time) 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 the pattern observed 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 <I>ZEB1/ZEB2</I> and acquired concomitant ability to repress new targets, including <I>LIFR</I>, a well-characterized metastasis suppressor. Our study highlights the importance of miRNA editing in gene regulation and suggests its potential as a biomarker for cancer prognosis and therapy.</P>