1. RNA editing enzyme ADAR2 regulates P-glycoprotein expression in murine breast cancer cells through the circRNA-miRNA pathway.
- Author
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Omata Y, Haraguchi M, Yoshinaga S, Ogino T, Okawa M, Tsuruta A, Koyanagi S, and Ohdo S
- Subjects
- Animals, Mice, Female, Cell Line, Tumor, Breast Neoplasms genetics, Breast Neoplasms metabolism, Breast Neoplasms pathology, RNA-Binding Proteins metabolism, RNA-Binding Proteins genetics, Drug Resistance, Neoplasm genetics, Antibiotics, Antineoplastic pharmacology, Adenosine Deaminase metabolism, Adenosine Deaminase genetics, MicroRNAs genetics, MicroRNAs metabolism, RNA, Circular genetics, RNA, Circular metabolism, RNA Editing, Doxorubicin pharmacology, Gene Expression Regulation, Neoplastic, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics
- Abstract
Among the various RNA modifications, adenosine-to-inosine RNA editing, catalyzed by adenosine deaminase acting on RNA (ADAR) family, ADAR1 and ADAR2, is the most common nucleotide conversion in mammalian cells. The pathological relevance of ADAR expression has been highlighted in recent human genetic studies. Low expression of the ADAR2 gene is correlated with a poor prognosis in breast cancer patients, but the underlying mechanism remains enigmatic. In this study, we constructed Adar2-knockdown (Adar2-KD) murine breast cancer 4T1 cells and observed their reduced susceptibility to chemotherapeutic drug doxorubicin. Downregulation of ADAR2 induced the expression of P-glycoprotein (P-gp), leading to a reduction in the intracellular accumulation of doxorubicin. The upregulation of P-gp occurred at the post-transcriptional level due to the decreased miR-195a-3p function. The search for the underlying cause of the induction of P-gp expression in Adar2-KD 4T1 cells led to the identification of circular RNA (circRNA) circHif1a as a sponge for miR-195a-3p. The enhanced expression of circHif1a inhibited miR-195a-3p function, resulting in the upregulation of P-gp expression. These results suggest that ADAR2 acts as a suppressor of circHif1a biogenesis and then allows miR-195a-3p to interfere with P-gp translation. Our findings may help to improve drug efficacy by clarifying the mechanism of chemoresistance in breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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