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CDK13 phosphorylates the translation machinery and promotes tumorigenic protein synthesis

Oncogene volume 42, pages 1321–1330 (2023)Cite this article

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Abstract

Cyclin-dependent kinase 13 (CDK13) has been suggested to phosphorylate RNA polymerase II and is involved in transcriptional activation. However, whether CDK13 catalyzes other protein substrates and how CDK13 contributes to tumorigenesis remain largely unclear. We here identify key translation machinery components, 4E-BP1 and eIF4B, as novel CDK13 substrates. CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. Polysome profiling analysis shows that MYC oncoprotein synthesis strictly depends on CDK13-regulated translation in colorectal cancer (CRC), and CDK13 is required for CRC cell proliferation. As mTORC1 is implicated in 4E-BP1 and eIF4B phosphorylation, inactivation of CDK13 in combination with the mTORC1 inhibitor rapamycin further dephosphorylates 4E-BP1 and eIF4B and blocks protein synthesis. As a result, dual inhibition of CDK13 and mTORC1 induces more profound tumor cell death. These findings clarify the pro-tumorigenic role of CDK13 by direct phosphorylation of translation initiation factors and enhancing protein synthesis. Therefore, therapeutic targeting of CDK13 alone or in combination with rapamycin may pave a new way for cancer treatment.

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Fig. 1: CDK13 interacts with the eIF4F complex in the cytoplasm.
Fig. 2: CDK13 directly phosphorylates 4EBP1 and eIF4B.
Fig. 3: CDK13 regulates protein synthesis.
Fig. 4: CDK13 regulates MYC mRNA translation and cancer cell proliferation.
Fig. 5: Synergistic targeting of CDK13 and mTORC1 in CRC cells and xenografts.

Data availability

The accession number for the RNA-Seq data reported in this study have been submitted to the Gene Expression Omnibus under accession number GSE224287.

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Acknowledgements

We thank all members of the Liu lab for helpful suggestions, and the Core Facility of Medical Research Institute at Wuhan University for providing immunofluorescence and histology platforms. This study was supported by grants from National Key Research and Development Program of China (2022YFA1103200), National Natural Science Foundation of China (81970152, 82025003, 82161138024) and Hubei Provincial Natural Science Fund for Creative Research Groups (2021CFA003).

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Author notes

  1. These authors contributed equally: Chao Wu, Ting Xie.

Authors and Affiliations

  1. Department of Hematology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, 430071, Wuhan, China

    Chao Wu, Ting Xie & Hudan Liu

  2. Frontier Science Center of Immunology and Metabolism, Wuhan University, 430071, Wuhan, China

    Chao Wu, Ting Xie, Ying Guo, Donghai Wang, Ruyi Han, Guoliang Qing & Hudan Liu

  3. Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, 430071, Wuhan, China

    Min Qiu & Kaiwei Liang

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Contributions

HL conceived and designed the study. HL and GQ supervised the study. HL and CW wrote the paper. CW and TX performed most of the experiments. KL and MQ performed phosphorylation mass spectrometry analysis and provided HCT116 CDK13 AS cells. YG and RH assisted with cell-based assays. DW provided technical assistance for mouse experiments and valuable help in RNA-Seq and proteomics data analysis.

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Correspondence to Hudan Liu.

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Wu, C., Xie, T., Guo, Y. et al. CDK13 phosphorylates the translation machinery and promotes tumorigenic protein synthesis. Oncogene 42, 1321–1330 (2023). https://doi.org/10.1038/s41388-023-02653-2

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