Hong H1, An O1, Chan THM1, Ng VHE1, Kwok HS1, Lin JS1, Qi L1,2, Han J1, Tay DJT1, Tang SJ1, Yang H1, Song Y1, Bellido Molias F1, Tenen DG1,3, Chen L1,4.
1 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
2 Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore.
3 Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
4 Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore.
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.