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KNSTRN promotes tumorigenesis and gemcitabine resistance by activating AKT in bladder cancer

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Abstract

KNSTRN is a component of the mitotic spindle, which was rarely investigated in tumorigenesis. AKT plays an essential role in tumorigenesis by modulating the phosphorylation of various substrates. The activation of AKT is regulated by PTEN and PIP3. Here, we prove KNSTRN is positively correlated with malignancy of bladder cancer and KNSTRN activates AKT phosphorylation at Thr308 and Ser473. More importantly, our study reveals that both KNSTRN and PTEN interact with PH domain of AKT at cell membrane. The amount of KNSTRN interacted with AKT is negatively related to PTEN. Furthermore, PIP3 pull-down assay proves that KNSTRN promoted AKT movement to PIP3. These data suggest KNSTRN may activate AKT phosphorylation by promoting AKT movement to PIP3 and alleviating PTEN suppression. Based on the activation of AKT phosphorylation, our study demonstrates that KNSTRN promotes bladder cancer metastasis and gemcitabine resistance in vitro and in vivo. Meanwhile, the effect of KNSTRN on tumorigenesis and gemcitabine resistance could be restored by AKT specific inhibitor MK2206 or AKT overexpression. In conclusion, we identify an oncogene KNSTRN that promotes tumorigenesis and gemcitabine resistance by activating AKT phosphorylation and may serve as a therapeutic target in bladder cancer.

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Fig. 1: Downregulation of KNSTRN inhibits bladder cancer metastasis in vitro and in vivo.
Fig. 2: Knockdown of KNSTRN promotes the chemosensitivity of gemcitabine to bladder cancer in vitro and in vivo.
Fig. 3: KNSTRN interacts with AKT and suppresses the activation of AKT.
Fig. 4: KNSTRN activates AKT phosphorylation by promoting AKT movement to PIP3 and alleviating PTEN suppression.
Fig. 5: KNSTRN promotes bladder cancer metastasis via AKT/GSK3β/Snail pathway.
Fig. 6: KNSTRN promotes gemcitabine resistance via AKT/FOXO1 pathway.
Fig. 7: The proposed model revealing KNSTRN promotes tumorigenesis and gemcitabine resistance by activating AKT in bladder cancer.

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Data availability

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

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Acknowledgements

The authors wish to acknowledge thank Dr Xiaoling Li from NIEHS for critical editing during the preparation of this paper. The excellent technical assistance of Ms Yayun Fang and Ms Danni Shan is gratefully acknowledged. We would like to acknowledge the the TCGA databases for free use. This work was supported by the Improvement Project for Theranostic ability on Difficulty miscellaneous disease (Tumor) from National Health Commission of China (ZLYNXM202006) and National Natural Science Foundation of China to XW (81772730), LJ (31900902) and GW (81902603).

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Authors and Affiliations

  1. Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China

    Yaoyi Xiong, Liang Chen, Huimin Xu, Tianchen Peng, Yongwen Luo, Yu Xiao & Xinghuan Wang

  2. Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China

    Lingao Ju, Gang Wang & Yu Xiao

  3. Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China

    Lingao Ju, Gang Wang & Yu Xiao

  4. Research Center of Wuhan for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China

    Lingao Ju, Gang Wang, Yu Xiao & Xinghuan Wang

  5. Division of Nephrology, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands

    Lushun Yuan

  6. Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, USA

    Liang Chen

  7. Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China

    Yu Xiao

  8. Medical Research Institute, Wuhan University, Wuhan, China

    Xinghuan Wang

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  1. Yaoyi Xiong
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Contributions

YX, LJ, YX and XW designed the experiments and wrote the paper. LY analyzed the data. YX, LJ, LY, GW, and YX revised the paper. HX and TP assisted with the mouse experiments and YL performed additional experiments. YX and XW conceived the study and coordinated the work.

Corresponding authors

Correspondence to Yu Xiao or Xinghuan Wang.

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Xiong, Y., Ju, L., Yuan, L. et al. KNSTRN promotes tumorigenesis and gemcitabine resistance by activating AKT in bladder cancer. Oncogene 40, 1595–1608 (2021). https://doi.org/10.1038/s41388-020-01634-z

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