Targeting the CK1α/CBX4 axis for metastasis in osteosarcoma

Nat Commun. 2020 Feb 28;11(1):1141. doi: 10.1038/s41467-020-14870-4.

Abstract

Osteosarcoma, an aggressive malignant cancer, has a high lung metastasis rate and lacks therapeutic target. Here, we reported that chromobox homolog 4 (CBX4) was overexpressed in osteosarcoma cell lines and tissues. CBX4 promoted metastasis by transcriptionally up-regulating Runx2 via the recruitment of GCN5 to the Runx2 promoter. The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα. Consistently, CK1α suppressed cell migration and invasion through inhibition of CBX4. There was a reverse correlation between CK1α and CBX4 in osteosarcoma tissues, and CK1α was a valuable marker to predict clinical outcomes in osteosarcoma patients with metastasis. Pyrvinium pamoate (PP) as a selective activator of CK1α could inhibit osteosarcoma metastasis via the CK1α/CBX4 axis. Our findings indicate that targeting the CK1α/CBX4 axis may benefit osteosarcoma patients with metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Casein Kinase Ialpha / genetics
  • Casein Kinase Ialpha / metabolism*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Ligases / antagonists & inhibitors*
  • Ligases / genetics
  • Ligases / metabolism*
  • Mice
  • Mutation
  • Neoplasm Metastasis
  • Osteosarcoma / drug therapy
  • Osteosarcoma / genetics
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology*
  • Phosphorylation / drug effects
  • Polycomb-Group Proteins / antagonists & inhibitors*
  • Polycomb-Group Proteins / genetics
  • Polycomb-Group Proteins / metabolism*
  • Promoter Regions, Genetic
  • Pyrvinium Compounds / pharmacology
  • Pyrvinium Compounds / therapeutic use
  • Survival Analysis
  • Tumor Necrosis Factor-alpha / pharmacology
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / drug effects
  • p300-CBP Transcription Factors / metabolism

Substances

  • Biomarkers, Tumor
  • Core Binding Factor Alpha 1 Subunit
  • Polycomb-Group Proteins
  • Pyrvinium Compounds
  • RUNX2 protein, human
  • Tumor Necrosis Factor-alpha
  • pyrvinium
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • STUB1 protein, human
  • Ubiquitin-Protein Ligases
  • Casein Kinase Ialpha
  • Ligases
  • CBX4 protein, human