Instituto, de Investigaciones Biomédicas "Alberto Sols"; Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain.
Department of Pathology, Harvard Medical School Initiative for RNA Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Mol Cancer. 2021 Sep 8;20(1):115. doi: 10.1186/s12943-021-01401-y.
Adenosine deaminases acting on RNA (ADARs) modify many cellular RNAs by catalyzing the conversion of adenosine to inosine (A-to-I), and their deregulation is associated with several cancers. We recently showed that A-to-I editing is elevated in thyroid tumors and that ADAR1 is functionally important for thyroid cancer cell progression. The downstream effectors regulated or edited by ADAR1 and the significance of ADAR1 deregulation in thyroid cancer remain, however, poorly defined.
We performed whole transcriptome sequencing to determine the consequences of ADAR1 deregulation for global gene expression, RNA splicing and editing. The effects of gene silencing or RNA editing were investigated by analyzing cell viability, proliferation, invasion and subnuclear localization, and by protein and gene expression analysis.
We report an oncogenic function for CDK13 in thyroid cancer and identify a new ADAR1-dependent RNA editing event that occurs in the coding region of its transcript. CDK13 was significantly over-edited (c.308A > G) in tumor samples and functional analysis revealed that this editing event promoted cancer cell hallmarks. Finally, we show that CDK13 editing increases the nucleolar abundance of the protein, and that this event might explain, at least partly, the global change in splicing produced by ADAR1 deregulation.
Overall, our data support A-to-I editing as an important pathway in cancer progression and highlight novel mechanisms that might be used therapeutically in thyroid and other cancers.
作用于 RNA 的腺苷脱氨酶（ADARs）通过催化腺苷向肌苷的转化来修饰许多细胞 RNA（A-to-I），其失调与多种癌症有关。我们最近表明，A-to-I 编辑在甲状腺肿瘤中升高，并且 ADAR1 对甲状腺癌细胞进展具有功能重要性。然而，ADAR1 失调在甲状腺癌中的下游效应物调节或编辑以及其意义仍未得到明确定义。
我们进行了全转录组测序，以确定 ADAR1 失调对全局基因表达、RNA 剪接和编辑的影响。通过分析细胞活力、增殖、侵袭和亚核定位以及蛋白质和基因表达分析，研究了基因沉默或 RNA 编辑的影响。
我们报告了 CDK13 在甲状腺癌中的致癌功能，并确定了一个新的 ADAR1 依赖性 RNA 编辑事件，该事件发生在其转录本的编码区域。CDK13 在肿瘤样本中被显著过度编辑（c.308A > G），功能分析表明该编辑事件促进了癌细胞特征。最后，我们表明 CDK13 编辑增加了蛋白质在核仁中的丰度，并且该事件可能至少部分解释了 ADAR1 失调产生的全局剪接变化。
总体而言，我们的数据支持 A-to-I 编辑作为癌症进展的重要途径，并强调了可能在甲状腺癌和其他癌症中具有治疗用途的新机制。
