Targeting the CK1a/CBX4 Axis for Metastasis in Osteosarcoma

Osteosarcoma is an aggressive malignant cancer that has a high rate of lung metastasis and lacks any 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 1a (CK1a) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFa. Consistently, CK1a suppressed cell migration and invasion through inhibition of CBX4. There was a reverse correlation between CK1a and CBX4 in osteosarcoma tissues, and either low CK1a or high CBX4 levels were correlated with poor prognoses of osteosarcoma patients. Pyrvinium pamoate (PP) as a selective activator of CK1a could inhibit osteosarcoma metastasis via the CK1a/CBX4 axis. Our findings provide evidence that targeting the CK1a/CBX4 axismay benefit osteosarcoma patients with metastasis.