Transcriptome Profiling of ADAR1 Targets in Triple-Negative Breast Cancer Cells Reveals Mechanisms for Regulating Growth and Invasion.
Transcriptome Profiling of ADAR1 Targets in Triple-Negative Breast Cancer Cells Reveals Mechanisms for Regulating Growth and Invasion.
复制标题
DOI：
10.1158/1541-7786.mcr-21-0604
复制
发表时间：
2022-06-03
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
ADAR催化双链RNA的腺苷到肌苷（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。ADAR在发育和疾病中起着重要作用，以前的工作表明ADAR 1在越来越多的癌症类型中是致癌的。在这里，我们表明ADAR 1是三阴性乳腺癌细胞的关键基因，因为ADAR 1缺失导致生长（活力和细胞周期进展），侵袭和乳腺球形成减少。全转录组测序分析表明，ADAR 1通过改变基因表达水平、A至I编辑和剪接来调节编码和非编码靶标。我们确定细丝蛋白B（FLNB chr 3：58156064）中的重新编码编辑降低了蛋白质的肿瘤抑制活性以促进生长和侵袭。我们还发现，一些肿瘤抑制microRNA在ADAR 1丢失后上调，并抑制细胞周期进展和侵袭。这项工作描述了三阴性乳腺癌中ADAR 1介导的肿瘤发生的几种新机制，为在这种几乎没有治疗选择的侵袭性癌症类型中靶向ADAR 1的策略提供了支持。
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 non-coding 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 microRNAs 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.