CK1δ/GSK3β/FBXW7α axis promotes degradation of the ZNF322A oncoprotein to suppress lung cancer progression
Journal
Oncogene
Journal Volume
36
Journal Issue
41
Pages
5722-5733
Date Issued
2017
Author(s)
Abstract
Overexpression of Cys2His2 zinc-finger 322A (ZNF322A) oncogenic transcription factor is associated with lung tumorigenesis. However, the mechanism of ZNF322A overexpression remains poorly understood. Here, we discover that protein stability of ZNF322A is regulated by coordinated phosphorylation and ubiquitination through the CK1δ/GSK3β/FBXW7α axis. CK1δ and GSK3β kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7α leading to ZNF322A protein destruction. Overexpression of FBXW7α induces ZNF322A protein degradation, thereby blocks ZNF322A transcription activity and suppresses ZNF322A-induced tumor growth and metastasis in vitro and in vivo. Clinically, overexpression of ZNF322A correlates with low FBXW7α or defective CK1δ/GSK3β-mediated phosphorylation in lung cancer patients. Multivariate Cox regression analysis indicates that patients with ZNF322A high/FBXW7 low expression profile can be used as an independent factor to predict the clinical outcome in lung cancer patients. Our results reveal a new mechanism of ZNF322A oncoprotein destruction regulated by the CK1δ/GSK3β/FBXW7α axis. Deregulation of this signaling axis results in ZNF322A overexpression and promotes cancer progression. ? 2017 Macmillan Publishers Limited, part of Springer Nature.
SDGs
Other Subjects
benzyloxycarbonylleucylleucylleucinal; casein kinase Idelta; F box and WD40 repeat domain containing 7 protein; F box protein; glycogen synthase kinase 3beta; oncoprotein; unclassified drug; zinc finger 322A; casein kinase Idelta; cell cycle protein; F box protein; FBXW7 protein, human; glycogen synthase kinase 3beta; oncoprotein; transcription factor; ubiquitin protein ligase; ZNF322a protein, human; Article; cancer growth; cancer inhibition; cancer patient; cancer prognosis; cancer staging; clinical outcome; controlled study; distant metastasis; female; HBEC cell line (bronchial); human; human cell; human tissue; immunohistochemistry; in vitro study; in vivo study; lung adenocarcinoma; lung cancer; lung carcinogenesis; major clinical study; male; NCI-H1299 cell line; NCI-H460 cell line; overall survival; priority journal; progression free survival; protein degradation; protein expression; protein interaction; protein phosphorylation; protein stability; squamous cell lung carcinoma; transcription regulation; tumor volume; ubiquitination; animal; disease course; drug screening; gene expression regulation; genetics; lung tumor; mouse; pathology; phosphorylation; Animals; Casein Kinase Idelta; Cell Cycle Proteins; Disease Progression; F-Box Proteins; Female; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 beta; Humans; Lung Neoplasms; Male; Mice; Oncogene Proteins; Phosphorylation; Transcription Factors; Ubiquitin-Protein Ligases; Xenograft Model Antitumor Assays
Publisher
Springer Nature
Type
journal article