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Mol Cell. 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.

Author information

1
Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Medical Research Institute, Wuhan University, Wuhan 430071, China.
2
Medical Research Institute, Wuhan University, Wuhan 430071, China.
3
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
4
Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Medical Research Institute, Wuhan University, Wuhan 430071, China. Electronic address: qingguoliang@whu.edu.cn.

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.

KEYWORDS:

ABT199; BI6727; Fbw7; Myc; PLK1; neuroblastoma; small cell lung carcinoma; targeted therapy; ubiquitination

PMID:
27773673
DOI:
10.1016/j.molcel.2016.09.016
[Indexed for MEDLINE]
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