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

  1. Zhaowei Wang
  2. Xiaoling Xia
  3. Jiaqi Li
  4. Tatsushi Igaki  Is a corresponding author
  1. Sun Yat-sen University, China
  2. South China Normal University, China
  3. 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

  1. Zhaowei Wang

    State Key Laboratory of Biocontrol, Sun Yat-sen University, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  2. 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.
  3. Jiaqi Li

    Laboratory of Genetics, Kyoto University, Kyoto, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. 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.
    ORCID icon "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.

Reviewing Editor

  1. Erika A Bach, New York University School of Medicine, United States

Publication history

  1. Received: January 25, 2022
  2. Preprint posted: February 11, 2022 (view preprint)
  3. Accepted: October 11, 2022
  4. Accepted Manuscript published: October 12, 2022 (version 1)
  5. Version of Record published: October 27, 2022 (version 2)

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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  1. Zhaowei Wang
  2. Xiaoling Xia
  3. Jiaqi Li
  4. Tatsushi Igaki
(2022)
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
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