CK1δ/GSK3β/FBXW7α axis promotes degradation of the ZNF322A oncoprotein to suppress lung cancer progression

S-Y Liao; C-W Chiang; C-H Hsu; Y-T Chen; J Jen; H-F Juan; W-W Lai; Y-C Wang

doi:10.1038/onc.2017.168

CK1δ/GSK3β/FBXW7α axis promotes degradation of the ZNF322A oncoprotein to suppress lung cancer progression

Oncogene. 2017 Oct 12;36(41):5722-5733. doi: 10.1038/onc.2017.168. Epub 2017 Jun 5.

Authors

S-Y Liao¹, C-W Chiang^{1

2}, C-H Hsu³, Y-T Chen⁴, J Jen⁴, H-F Juan⁵, W-W Lai⁶, Y-C Wang^{1

4}

Affiliations

¹ Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
² Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
³ Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan.
⁴ Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁵ Department of Life Science, Institute of Molecular and Cellular Biology, Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
⁶ Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

PMID: 28581525
DOI: 10.1038/onc.2017.168

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.

MeSH terms

Animals
Casein Kinase Idelta / genetics*
Cell Cycle Proteins / genetics*
Disease Progression
F-Box Proteins / genetics*
F-Box-WD Repeat-Containing Protein 7
Female
Gene Expression Regulation, Neoplastic
Glycogen Synthase Kinase 3 beta / genetics*
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / pathology
Male
Mice
Oncogene Proteins / genetics*
Phosphorylation
Transcription Factors / genetics*
Ubiquitin-Protein Ligases / genetics*
Xenograft Model Antitumor Assays

Substances

Cell Cycle Proteins
F-Box Proteins
F-Box-WD Repeat-Containing Protein 7
FBXW7 protein, human
Oncogene Proteins
Transcription Factors
ZNF322 protein, human
Ubiquitin-Protein Ligases
Casein Kinase Idelta
Glycogen Synthase Kinase 3 beta