ADAR1 promotes robust hypoxia signaling via distinct regulation of multiple HIF-1α-inhibiting factors

Chung Pei Ma, Hsuan Liu, Ian Yi-Feng Chang, Wan Cheng Wang, Yi Tung Chen, Shao Min Wu, Hui Wen Chen, Yu Ping Kuo, Chieh Tien Shih, Chuan Yun Li, Bertrand Chin Ming Tan*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

15 Scopus citations

Abstract

Adenosine deaminase acting on RNA (ADAR)-catalyzed adenosine-to-inosine RNA editing is potentially dysregulated in neoplastic progression. However, how this transcriptome recoding process is functionally correlated with tumorigenesis remains largely elusive. Our analyses of RNA editome datasets identify hypoxia-related genes as A-to-I editing targets. In particular, two negative regulators of HIF-1A—the natural antisense transcript HIF1A-AS2 and the ubiquitin ligase scaffold LIMD1—are directly but differentially modulated by ADAR1. We show that HIF1A-AS2 antagonizes the expression of HIF-1A in the immediate-early phase of hypoxic challenge, likely through a convergent transcription competition in cis. ADAR1 in turn suppresses transcriptional progression of the antisense gene. In contrast, ADAR1 affects LIMD1 expression post-transcriptionally, by interfering with the cytoplasmic translocation of LIMD1 mRNA and thus protein translation. This multi-tier regulation coordinated by ADAR1 promotes robust and timely accumulation of HIF-1α upon oxygen depletion and reinforces target gene induction and downstream angiogenesis. Our results pinpoint ADAR1-HIF-1α axis as a hitherto unrecognized key regulator in hypoxia.

Original languageEnglish
Article numbere47107
JournalEMBO Reports
Volume20
Issue number5
DOIs
StatePublished - 05 2019

Bibliographical note

Publisher Copyright:
© 2019 The Authors

Keywords

  • ADAR
  • HIF-1α
  • LIMD1
  • RNA editing
  • antisense transcription
  • hypoxia

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