State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Nat Commun. 2020 Feb 28;11(1):1141. doi: 10.1038/s41467-020-14870-4.
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.
成骨肉瘤是一种侵袭性恶性肿瘤，具有较高的肺转移率，且缺乏治疗靶点。在这里，我们报道了染色质盒蛋白 4（CBX4）在成骨肉瘤细胞系和组织中过表达。CBX4 通过募集 GCN5 到 Runx2 启动子，转录地上调 Runx2，从而促进转移。CK1α 对 CBX4 的 T437 进行磷酸化，促进了其在 K178 和 K280 上的泛素化和随后由 CHIP 介导的降解，而 TNFα 可减少 CBX4 的这种磷酸化。同样，CK1α 通过抑制 CBX4 抑制细胞迁移和侵袭。在成骨肉瘤组织中，CK1α 与 CBX4 呈负相关，CK1α 是预测转移性成骨肉瘤患者临床结局的有价值标志物。吡嗪酰胺（PP）作为 CK1α 的选择性激活剂，可通过 CK1α/CBX4 轴抑制成骨肉瘤转移。我们的研究结果表明，靶向 CK1α/CBX4 轴可能有益于转移性成骨肉瘤患者。
