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. 2016 Nov 3;64(3):493-506.
doi: 10.1016/j.molcel.2016.09.016. Epub 2016 Oct 20.

Polo-like Kinase-1 Regulates Myc Stabilization and Activates a Feedforward Circuit Promoting Tumor Cell Survival

Daibiao Xiao  1 , Ming Yue  2 , Hexiu Su  2 , Ping Ren  2 , Jue Jiang  2 , Feng Li  3 , Yufeng Hu  2 , Haining Du  3 , Hudan Liu  1 , Guoliang Qing  4
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Free article

Polo-like Kinase-1 Regulates Myc Stabilization and Activates a Feedforward Circuit Promoting Tumor Cell Survival

Daibiao Xiao et al. Mol Cell. .
Free article

Abstract

MYCN amplification in human cancers predicts poor prognosis and resistance to therapy. However, pharmacological strategies that directly target N-Myc, the protein encoded by MYCN, remain elusive. Here, we identify a molecular mechanism responsible for reciprocal activation between Polo-like kinase-1 (PLK1) and N-Myc. PLK1 specifically binds to the SCFFbw7 ubiquitin ligase, phosphorylates it, and promotes its autopolyubiquitination and proteasomal degradation, counteracting Fbw7-mediated degradation of N-Myc and additional substrates, including cyclin E and Mcl1. Stabilized N-Myc in turn directly activates PLK1 transcription, constituting a positive feedforward regulatory loop that reinforces Myc-regulated oncogenic programs. Inhibitors of PLK1 preferentially induce potent apoptosis of MYCN-amplified tumor cells from neuroblastoma and small cell lung cancer and synergistically potentiate the therapeutic efficacies of Bcl2 antagonists. These findings reveal a PLK1-Fbw7-Myc signaling circuit that underlies tumorigenesis and validate PLK1 inhibitors, alone or with Bcl2 antagonists, as potential effective therapeutics for MYC-overexpressing cancers. VSports手机版.

Keywords: ABT199; BI6727; Fbw7; Myc; PLK1; neuroblastoma; small cell lung carcinoma; targeted therapy; ubiquitination V体育安卓版. .

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