Genomic Landscape and Potential Regulation of RNA Editing in Drug Resistance

Abstract

Adenosine‐to‐inosine RNA editing critically affects the response of cancer therapies. However, comprehensive identification of drug resistance‐related RNA editing events and systematic understanding of how RNA editing mediates anticancer drug resistance remain unclear. Here, 7157 differential editing sites (DESs) are identified from 98 127 informative RNA editing sites in tumor tissues, many of which are validated in cancer cell lines. Diverse editing patterns of DESs are discovered in resistant samples, which could not be fully explained by adenosine deaminase acting on RNA enzymes. Some RNA‐binding proteins are identified that potentially regulate these editing events. Notably, the DESs are significantly enriched in 3’‐untranslated regions (3’‐UTRs). The impact of DESs in 3’‐UTR on the microRNA (miRNA) regulations is explored, and some triplets (DES, miRNA, and gene) that may contribute to drug resistance are identified. In addition, it is determined that the functions of genes enriched with DESs are associated with drug resistance, such as apoptosis, drug metabolism, and DNA synthesis involved in DNA repair. An online resource (http://www.jianglab.cn/REDR/) to support convenient retrieval of DESs is also built. The findings reveal the landscape and potential regulatory mechanism of RNA editing in drug resistance, providing new therapeutic targets for reversing drug resistance.

A Comprehensive Analysis of the Effect of A>I(G) RNA-Editing Sites on Genotoxic Drug Response and Progression in Breast Cancer

“…Within our BC cell lines, a positive correlation emerged between ADAR1 expression and the global editing index. A trend also was found in cancer cell lines [31] and in patients with acute myeloid leukemia (AML) [32]. This correlation suggests that the global editing index may only partially explain the RNA-editing activity of ADAR1, emphasizing the need for a more targeted approach focusing on specific RNA-edited sites.…”

“…We describe a comprehensive landscape of DESs associated with drug sensitivity. Recently, in a study about A>I(G) RNA editing across all available cancer cell lines, only two RNA-edited sites, Chr19:58355670 (A/G) in ZNF587B and Chr20:36147563 (T/C) in BLCAP, were associated with sensitivity to doxorubicin specifically in BC cell lines [31]. In contrast, our study delves deeper into the RNA-editing landscape of BC cell lines, offering a thorough characterization of an extensive and stringent list of DESs linked to genotoxic drug sensitivity.…”

Global characterization of RNA editing in genetic regulation of multiple ovarian cancer subtypes

“…also investigated different brain regions linking spatiotemporal changes in cell type and editing levels to editing variation and genetic regulation. 18 , 19 Furthermore, RNA editing has been associated with drug resistance in tumors, 20 and ADAR1-mediated SCD1 RNA editing has been shown to drive drug resistance in gastric cancer. 21 Overall, the progression of OV is hindered by a combination of genetic and epigenetic changes, drug resistance, and increased genetic diversity in tumor cells.…”