Harvard Medical School Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Instituto de Investigaciones Biomédicas "Alberto Sols"; Cosejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain.
Mol Cancer Res. 2022 Jun 3;20(6):960-971. doi: 10.1158/1541-7786.MCR-21-0604.
ADARs catalyze adenosine-to-inosine (A-to-I) editing of double-stranded RNA and regulate global gene expression output through interactions with RNA and other proteins. ADARs play important roles in development and disease, and previous work has shown that ADAR1 is oncogenic in a growing list of cancer types. Here we show that ADAR1 is a critical gene for triple-negative breast cancer cells, as ADAR1 loss results in reduced growth (viability and cell cycle progression), invasion, and mammosphere formation. Whole transcriptome sequencing analyses demonstrate that ADAR1 regulates both coding and noncoding targets by altering gene expression level, A-to-I editing, and splicing. We determine that a recoding edit in filamin B (FLNB chr3:58156064) reduces the tumor suppressive activities of the protein to promote growth and invasion. We also show that several tumor suppressor miRNAs are upregulated upon ADAR1 loss and suppress cell-cycle progression and invasion. This work describes several novel mechanisms of ADAR1-mediated oncogenesis in triple-negative breast cancer, providing support to strategies targeting ADAR1 in this aggressive cancer type that has few treatment options.
Targeting ADAR1 and thus downstream FLNB editing and miRNA regulation represents a possible novel therapeutic strategy in triple-negative breast cancer.
ADARs 催化双链 RNA 中的腺苷向肌苷（A-to-I）编辑，并通过与 RNA 和其他蛋白质的相互作用调节全局基因表达输出。ADARs 在发育和疾病中发挥重要作用，先前的工作表明 ADAR1 在越来越多的癌症类型中具有致癌作用。在这里，我们表明 ADAR1 是三阴性乳腺癌细胞的关键基因，因为 ADAR1 的缺失会导致生长（活力和细胞周期进程）、侵袭和乳腺球体形成减少。全转录组测序分析表明，ADAR1 通过改变基因表达水平、A-to-I 编辑和剪接来调节编码和非编码靶标。我们确定，在细丝蛋白 B (FLNB chr3:58156064) 中的重编码编辑降低了该蛋白的肿瘤抑制活性，从而促进了生长和侵袭。我们还表明，ADAR1 缺失后几种肿瘤抑制 miRNA 上调，并抑制细胞周期进程和侵袭。这项工作描述了 ADAR1 在三阴性乳腺癌中介导的几种新的致癌机制，为针对这种侵袭性强且治疗选择有限的癌症类型中的 ADAR1 提供了支持。
靶向 ADAR1 及其下游 FLNB 编辑和 miRNA 调节可能代表三阴性乳腺癌的一种新的潜在治疗策略。
