Targeting the CK1α/CBX4 axis for metastasis in osteosarcoma

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 1 alpha (CK1 alpha) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNF alpha. Consistently, CK1 alpha suppressed cell migration and invasion through inhibition of CBX4. There was a reverse correlation between CK1 alpha and CBX4 in osteosarcoma tissues, and CK1 alpha was a valuable marker to predict clinical outcomes in osteosarcoma patients with metastasis. Pyrvinium pamoate (PP) as a selective activator of CK1 alpha could inhibit osteosarcoma metastasis via the CK1 alpha/CBX4 axis. Our findings indicate that targeting the CK1 alpha/CBX4 axis may benefit osteosarcoma patients with metastasis.