Tumor elimination by clustered microRNAs miR-306 and miR-79 via non-canonical activation of JNK signaling

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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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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.

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Zhaowei Wang

State Key Laboratory of Biocontrol, Sun Yat-sen University, Shenzhen, China

Competing interests
The authors declare that no competing interests exist.
Xiaoling Xia

Guangzhou Key Laboratory of Insect Development Regulation and Application Research, South China Normal University, Guangzhou, China

Competing interests
The authors declare that no competing interests exist.
Jiaqi Li

Laboratory of Genetics, Kyoto University, Kyoto, Japan

Competing interests
The authors declare that no competing interests exist.
Tatsushi Igaki

Laboratory of Genetics, Kyoto University, Kyoto, Japan

For correspondence
igaki.tatsushi.4s@kyoto-u.ac.jp

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5839-9526

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.

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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.