Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore.
Nucleic Acids Res. 2018 Sep 6;46(15):7953-7969. doi: 10.1093/nar/gky396.
Adenosine-to-inosine (A-to-I) RNA editing entails the enzymatic deamination of adenosines to inosines by adenosine deaminases acting on RNA (ADARs). Dysregulated A-to-I editing has been implicated in various diseases, including cancers. However, the precise factors governing the A-to-I editing and their physiopathological implications remain as a long-standing question. Herein, we unravel that DEAH box helicase 9 (DHX9), at least partially dependent of its helicase activity, functions as a bidirectional regulator of A-to-I editing in cancer cells. Intriguingly, the ADAR substrate specificity determines the opposing effects of DHX9 on editing as DHX9 silencing preferentially represses editing of ADAR1-specific substrates, whereas augments ADAR2-specific substrate editing. Analysis of 11 cancer types from The Cancer Genome Atlas (TCGA) reveals a striking overexpression of DHX9 in tumors. Further, tumorigenicity studies demonstrate a helicase-dependent oncogenic role of DHX9 in cancer development. In sum, DHX9 constitutes a bidirectional regulatory mode in A-to-I editing, which is in part responsible for the dysregulated editome profile in cancer.
腺嘌呤到次黄嘌呤（A-to-I）RNA 编辑涉及由作用于 RNA 的腺苷脱氨酶（ADARs）将腺嘌呤酶促脱氨为次黄嘌呤。A-to-I 编辑失调与各种疾病有关，包括癌症。然而，调节 A-to-I 编辑的精确因素及其生理病理学意义仍然是一个长期存在的问题。在此，我们揭示 DEAH 盒解旋酶 9（DHX9）至少部分依赖其解旋酶活性，作为癌细胞中 A-to-I 编辑的双向调节剂发挥作用。有趣的是，ADAR 底物特异性决定了 DHX9 对编辑的相反影响，因为 DHX9 沉默优先抑制 ADAR1 特异性底物的编辑，而增强 ADAR2 特异性底物的编辑。对来自癌症基因组图谱 (TCGA) 的 11 种癌症类型的分析显示，DHX9 在肿瘤中明显过表达。此外，肿瘤发生研究表明 DHX9 在癌症发展中具有依赖解旋酶的致癌作用。总之，DHX9 在 A-to-I 编辑中构成了一种双向调节模式，部分负责癌症中失调的编辑组谱。
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