PT  - JOURNAL ARTICLE
AU  - Zhaowei Wang
AU  - Xiaoling Xia
AU  - Tatsushi Igaki
TI  - Tumor elimination by clustered microRNAs miR-306 and miR-79 via non-canonical activation of JNK signaling
AID  - 10.1101/2022.02.11.480121
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.02.11.480121
4099  - http://biorxiv.org/content/early/2022/02/11/2022.02.11.480121.short
4100  - http://biorxiv.org/content/early/2022/02/11/2022.02.11.480121.full
AB  - 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 no significant 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 Drosophila ring finger protein 146 (dRNF146). We found that DRNF146 promotes degradation of tankyrase (Tnks), an ADP-ribose polymerase that promotes JNK activation in a non-canonical manner. Thus, downregulation of dRNF146 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.Competing Interest StatementThe authors have declared no competing interest.