Abstract
Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer-related deaths. However, there are few effective therapeutic targets for CRC patients. Here, we found that CDK15 was highly expressed in human CRC and negatively correlated with patient prognosis and overall survival in tissue microarray. Knockdown of CDK15 suppressed cell proliferation and anchorage-independent growth of CRC cells and inhibited tumor growth in cell line-derived xenograft (CDX) model. Importantly, knockout of CDK15 in mice retarded AOM/DSS-induced tumorigenesis and CDK15 silencing by lentivirus significantly suppressed tumor progression in patient-derived xenograft (PDX) model. Mechanistically, CDK15 could bind PAK4 and phosphorylate PAK4 at S291 site. Phosphorylation of PAK4 at the S291 residue promoted cell proliferation and anchorage-independent growth through β-catenin/c-Myc, MEK/ERK signaling pathway in CRC. Moreover, inhibition of PAK4 reversed the tumorigenic function of CDK15 in CRC cells and pharmacological targeting PAK4 suppressed tumor growth in PDX models. Thus, our data reveal the pivotal role of CDK15 in CRC progression and demonstrate CDK15 promotes CRC tumorigenesis by phosphorylating PAK4. Hence, the CDK15-PAK4 axis may serve as a novel therapeutic target for CRC.
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Acknowledgements
We thank Dr. Fangfang Liu for advice on AOM/DSS-induced mice model. We are grateful to Wenna Nie for analysis of mass spectrometry and Ran Yang for preparation of immunohistochemical section.
Funding
This work was supported by National Natural Science Foundation of China (No. 82073075, 81802795, 31301144); Key scientific research project plan of colleges and universities in Henan Province (No. 18A310034); Science and Technology Project of Henan Province (No. 182102310324, 202102310206); Training plan for young backbone teachers of Zhengzhou University (No. 2018ZDGGJS037); Training plan for young backbone teachers of Henan Province (No. 2020GGJS010); Basic research and Cultivation Fund for young teachers of Zhengzhou University (No. JC202035023); Science and technology innovation talents support plan of Henan Province (No.21HASTIT048).
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CTH wrote the manuscript. CTH and RJD participated in designing the research and in analyzing data. CTH, XCJ, and QW performed in vivo study and participated in mouse experiment; NY, LY, LTZ, XJL, and MXX performed mouse experiments and helped with in vitro studies. YQ conducted the computer docking model. PX performed the pathological studies. YW performed the immunohistochemical studies. XL and ZGD conceived the study. All authors critically revised manuscript and approved the final version.
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Written informed consent was obtained from all subjects. All animal experiments were conducted in agreement with the Guide for the Care and Use of Laboratory Animals and approved by the Ethics Committee of Zhengzhou University (Zhengzhou, Henan, China).
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Huang, C., Du, R., Jia, X. et al. CDK15 promotes colorectal cancer progression via phosphorylating PAK4 and regulating β-catenin/ MEK-ERK signaling pathway. Cell Death Differ 29, 14–27 (2022). https://doi.org/10.1038/s41418-021-00828-6
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DOI: https://doi.org/10.1038/s41418-021-00828-6
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