CEP63 upregulates YAP1 to promote colorectal cancer progression through stabilizing RNA binding protein FXR1
CEP63 upregulates YAP1 to promote colorectal cancer progression through stabilizing RNA binding protein FXR1
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CEP63 通过稳定 RNA 结合蛋白 FXR1 上调 YAP1，从而促进结直肠癌进展。
DOI：
10.1038/s41388-022-02439-y
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发表时间：
2022-08-22
期刊：
影响因子：
8
通讯作者：
Wang, Feng-Wei
中科院分区：
文献类型：
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作者：
Ling, Han;Cao, Chen-Hui;Wang, Feng-Wei
中心体组分的异常调控可导致染色体不稳定和肿瘤的发生。中心体蛋白63（centrosomalprotein 63，CEP 63）是中心体组装的重要成员。然而，CEP 63在癌症发病机制中的参与仍不清楚。在这里，我们确定CEP 63作为RNA结合蛋白（RBP）的重要介质，以促进其在结直肠癌（CRC）中的RNA靶点的调节。我们证明了CEP 63蛋白在一个大的结直肠癌组织队列中上调，并预测预后不良，USP 36被鉴定为通过增强其K48依赖性去泛素化来稳定CEP 63。CEP 63过表达在体外和体内促进CRC细胞的增殖和肿瘤生长。此外，我们发现CEP 63可以通过结合并抑制CRC细胞中RBP FXR 1的K63-遍在化降解来增强YAP 1表达，从而促进癌症干细胞样细胞特性。重要的是，我们进一步验证了FXR 1的KH结构域是CEP 63和FXR 1之间相互作用所必需的。此外，微管马达蛋白可以与CEP 63和FXR 1形成复合物，以介导FXR 1对RNA靶标的调节。此外，我们还证实了CEP 63可以结合和调节多种RBP。总之，我们的研究结果揭示了一个未被认识的CEP 63/RBP/RNA轴，CEP 63可能作为接头促进RBP复合物的形成以调节RNA的进展，并发现CEP 63参与信号转导和RNA调节的作用，为CRC患者提供潜在的治疗靶点。
Abnormal regulation of centrosome components can induce chromosome instability and tumorigenesis. Centrosomal protein 63 (CEP63) is a vital member for assembling centrosome. Yet, the involvement of CEP63 in cancer pathogenesis remains unclear. Here we identify CEP63 as an important mediator for RNA-binding proteins (RBPs) to facilitate regulation on their RNA targets in colorectal cancer (CRC). We demonstrate that CEP63 protein is upregulated in a large cohort of colorectal cancer tissues and predicts poor prognosis, and USP36 is identified for stabilizing CEP63 by enhancing its K48-dependent deubiquitination. CEP63 overexpression promotes the proliferation and tumor growth of CRC cells in vitro and in vivo. Furthermore, we find that CEP63 can promote cancer stem-like cell properties by enhancing YAP1 expression through binding with and inhibiting the K63-ubiquitylation degradation of RBP FXR1 in CRC cells. Importantly, we further verify that the KH domain of FXR1 is necessary for the interaction between CEP63 and FXR1. Moreover, microtube motor proteins can form a complex with CEP63 and FXR1 to mediate the regulation of FXR1 on RNA targets. Additionally, we also confirm that CEP63 can bind and regulate multiple RBPs. In conclusion, our findings unveil an unrecognized CEP63/RBPs/RNA axis that CEP63 may perform as an adapter facilitating the formation of RBPs complex to regulate RNA progression and discover the role of CEP63 involved in signal transduction and RNA regulation, providing potential therapeutic target for CRC patients.