Targeting the CK1α/CBX4 axis for metastasis in osteosarcoma
Targeting the CK1α/CBX4 axis for metastasis in osteosarcoma
复制标题
靶向 CK1 α/CBX4 轴促进骨肉瘤转移
DOI：
10.1038/s41467-020-14870-4
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发表时间：
2020-02-28
影响因子：
16.6
通讯作者：
Kang, Tiebang
中科院分区：
文献类型：
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作者：
Wang, Xin;Qin, Ge;Kang, Tiebang
骨肉瘤是一种侵袭性恶性肿瘤，肺转移率高，缺乏治疗靶点。在这里，我们报道了色盒同源物4 （CBX4）在骨肉瘤细胞系和组织中过表达。CBX4通过募集GCN5到Runx2启动子，通过转录上调Runx2来促进转移。酪蛋白激酶1 α (CK1 α)在T437位点磷酸化CBX4，促进了其在K178和K280位点的泛素化，并随后被CHIP降解，并且CBX4的磷酸化可以被TNF α降低。一致地，CK1 α通过抑制CBX4抑制细胞迁移和侵袭。骨肉瘤组织中CK1 α与CBX4呈负相关，CK1 α是预测骨肉瘤转移患者临床预后的有价值的标志物。pamoate Pyrvinium （PP）作为CK1 α的选择性激活剂可以通过CK1 α /CBX4轴抑制骨肉瘤的转移。我们的研究结果表明，靶向CK1 α /CBX4轴可能有利于骨肉瘤转移患者。
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.