Oncotarget

Research Papers:

microRNA-206 impairs c-Myc-driven cancer in a synthetic lethal manner by directly inhibiting MAP3K13

Han Han, Yuxing Chen, Li Cheng, Edward V. Prochownik, Youjun Li _

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Oncotarget. 2016; 7:16409-16419. https://doi.org/10.18632/oncotarget.7653

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Abstract

Han Han1, Yuxing Chen1, Li Cheng1, Edward V. Prochownik2, Youjun Li1

1College of Life Sciences, Medical Research Institute, Wuhan University, Wuhan 430072, China

2Division of Hematology/Oncology, Children’s Hospital of Pittsburgh of UPMC and The Department of Microbiology and Molecular Genetics, The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224, USA

Correspondence to:

Youjun Li, e-mail: liy7@whu.edu.cn

Keywords: Myc, microRNA, MAP3K13, breast cancer

Received: September 27, 2015     Accepted: February 05, 2016     Published: February 24, 2016

ABSTRACT

c-Myc (Myc) is one of the most frequently dysregulated oncogenic transcription factors in human cancer. By functionally screening a microRNA (miR) library, we identified miR-206 as being a synthetic lethal in Myc over-expressing human cancer cells. miR-206 inhibited MAP3K13, which resulted in Myc protein de-stabilization, and an inhibition of anchorage-independent growth and in vivo tumorigenesis by Myc over-expressing human cancer cells. Eliminating MAP3K13 by shRNA recapitulated the effects caused by miR-206, thus supporting the idea that miR-206’s effect on Myc was mediated through MAP3K13. Conversely, enforced expression of MAP3K13 stabilized Myc by promoting its N-terminal phosphorylation and enhancing its transcriptional activity. Gene expression analyses of breast cancers expressing high levels of Myc indicated that low miR-206 expression and high MAP3K13 expression correlated with poor patient survival. The critical link between miR-206 and MAP3K13 in the development of Myc over-expressing human cancers suggests potential points of therapeutic intervention for this molecular sub-category.


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