Tumor elimination by clustered microRNAs miR-306 and miR-79 via non-canonical activation of JNK signaling
Abstract
JNK signaling plays a critical role in both tumor promotion and tumor suppression. Here, we identified clustered microRNAs (miRNAs) miR-306 and miR-79 as novel tumor-suppressor miRNAs that specifically eliminate JNK-activated tumors in Drosophila. While showing only a slight effect on normal tissue growth, miR-306 and miR-79 strongly suppressed growth of multiple tumor models including malignant tumors caused by Ras activation and cell polarity defects. Mechanistically, these miRNAs commonly target the mRNA of an E3 ubiquitin ligase ring finger protein 146 (RNF146). We found that RNF146 promotes degradation of tankyrase (Tnks), an ADP-ribose polymerase that promotes JNK activation in a non-canonical manner. Thus, downregulation of RNF146 by miR-306 and miR-79 leads to hyper-enhancement of JNK activation. Our data show that, while JNK activity is essential for tumor growth, elevation of miR-306 or miR-79 overactivate JNK signaling to the lethal level via non-canonical JNK pathway and thus eliminate tumors, providing a new miRNA-based strategy against cancer.
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Funding
MEXT/JSPS KAKENHI (20H05320)
- Tatsushi Igaki
MEXT/JSPS KAKENHI (21H05284)
- Tatsushi Igaki
MEXT/JSPS KAKENHI (21H05039)
- Tatsushi Igaki
Japan Agency for Medical Research and Development (Project for Elucidating and Controlling Mechanisms of Aging and Longevity,20gm5010001)
- Tatsushi Igaki
Takeda Science Foundation
- Tatsushi Igaki
Fundamental Research Funds for the Central Universities (Sun Yat-sen University,22hytd05)
- Zhaowei Wang
Naito Foundation
- Tatsushi Igaki
Japan Society for the Promotion of Science (Postdoctoral Fellowships for Research in Japan)
- Zhaowei Wang
China Scholarship Council (for Research in Japan)
- Xiaoling Xia
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Wang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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