Tumor elimination by clustered microRNAs miR-306 and miR-79 via non-canonical activation of JNK signaling
- Sun Yat-sen University, China
- South China Normal University, China
- Kyoto University, Japan
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.
Data availability
All relevant data are within the paper and its Supporting Information files. All the numerical data that are represented as a graph in a figure are provided in the Source Data file.
Article and author information
Author details
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.
Metrics
-
- 6
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Tumor elimination by clustered microRNAs miR-306 and miR-79 via non-canonical activation of JNK signaling
eLife 11:e77340.
https://doi.org/10.7554/eLife.77340
