title: Polo-like Kinase-1 Regulates Myc Stabilization and Activates a Feedforward Circuit Promoting Tumor Cell Survival.
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 SCFFbw7ubiquitin 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.
authors: Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Medical Research Institute, Wuhan University, Wuhan 430071, China.
authors: Daibiao
authors: D
authors: Xiao
authors: Medical Research Institute, Wuhan University, Wuhan 430071, China.
authors: Ming
authors: M
authors: Yue
authors: Medical Research Institute, Wuhan University, Wuhan 430071, China.
authors: Hexiu
authors: H
authors: Su
authors: Medical Research Institute, Wuhan University, Wuhan 430071, China.
authors: Ping
authors: P
authors: Ren
authors: Medical Research Institute, Wuhan University, Wuhan 430071, China.
authors: Jue
authors: J
authors: Jiang
authors: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors: Feng
authors: F
authors: Li
authors: Medical Research Institute, Wuhan University, Wuhan 430071, China.
authors: Yufeng
authors: Y
authors: Hu
authors: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors: Haining
authors: H
authors: Du
authors: Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Medical Research Institute, Wuhan University, Wuhan 430071, China.
authors: Hudan
authors: H
authors: Liu
authors: Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Medical Research Institute, Wuhan University, Wuhan 430071, China. Electronic address: qingguoliang@whu.edu.cn.
authors: Guoliang
authors: G
authors: Qing
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008819:Mice, Nude; D000071447:N-Myc Proto-Oncogene Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D016019:Survival Analysis; D014158:Transcription, Genetic; D047368:Tumor Burden / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D000071447:N-Myc Proto-Oncogene Protein; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011621:Pteridines; D034741:RNA, Small Interfering; D013449:Sulfonamides; D044767:Ubiquitin-Protein Ligases; D000097869:Polo-Like Kinase 1; C000595707:BCL2 protein, human; C541363:BI 6727; C513273:FBXW7 protein, human; C459801:MYCN protein, human; C579720:venetoclax
keywords: ABT199; BI6727; Fbw7; Myc; PLK1; neuroblastoma; small cell lung carcinoma; targeted therapy; ubiquitination