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CEP63 upregulates YAP1 to promote colorectal cancer progression through stabilizing RNA binding protein FXR1

Abstract

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.

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Fig. 1: CEP63 is highly expressed in CRC patient tissues and is associated with a poor prognosis.
Fig. 2: USP36 inhibits K48-linked polyubiquitination of CEP63.
Fig. 3: CEP63 promotes colorectal cancer stem cell phenotype.
Fig. 4: YAP1 silencing inhibits CEP63-induced colorectal cancer stem cell phenotype.
Fig. 5: FXR1 positively impacts the biological function of CEP63.
Fig. 6: CEP63 binds with the KH domain of FXR1.
Fig. 7: CEP63 deubiquitinates and stabilizes FXR1.
Fig. 8: FXR1 interacts with YAP1 mRNA and stabilizes it.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by grants from the National Key R&D Program of China (grant number 2021YFA1300201); the National Natural Science Foundation of China (grant numbers 81972227, 81730072, 82072608, 81872001, 81903007 and 82002467); the Guangzhou Science and Technology Plan Projects (grant number 201904020044) and the China Postdoctoral Science Foundation (2020M672999).

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F-WW conceived and devised the study. HL and F-WW designed the experiments and analysis. HL, C-HC, KH, Y-RL, X-DM, J-HC, J-WC, and SL performed the experiments. J-LL performed bioinformatics and statistical analysis. HL, C-HC, KH, and Y-RL analyzed and interpreted the data. Y-JF and Z-ZP provided CRC patients tissue samples and clinical information. F-WW and DX supervised the research, and HL together with F-WW wrote the manuscript. All authors approved the submitted manuscript.

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Correspondence to Dan Xie or Feng-wei Wang.

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Ling, H., Cao, Ch., Han, K. et al. CEP63 upregulates YAP1 to promote colorectal cancer progression through stabilizing RNA binding protein FXR1. Oncogene 41, 4433–4445 (2022). https://doi.org/10.1038/s41388-022-02439-y

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