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Stabilization of AURKA by the E3 ubiquitin ligase CBLC in lung adenocarcinoma

Oncogene volume 41, pages 1907–1917 (2022)Cite this article

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Abstract

CBL family proteins (CBL, CBLB and CBLC in mammals) are E3 ubiquitin ligases of protein tyrosine kinases. CBL mediates the lysosomal degradation of activated EGFR through K63-linked ubiquitination, while CBLC has an oncogenic function by positively regulating EGFR activation through K6 and K11-linked ubiquitination in EGFR mutant lung adenocarcinoma (LAD). Here, we used immunoprecipitation and mass spectrometry to study the CBLC interactome, and found that CBLC is also involved in cell cycle regulation by stabilizing Aurora kinase A (AURKA). CBLC interacted with the kinase domain of AURKA and positively regulated the stability of AURKA by conjugating monoubiquitination and K11/K63-linked polyubiquitination, which are protective from degrading K11/K48 polyubiquitination. CBLC depletion markedly decreased the half-life of AURKA in cycloheximide-treated LAD cells. When LAD cells were synchronized with double thymidine block at the G1/S boundary and then released into mitotic arrest, CBLC depletion delayed the accumulation and activation of AURKA and prevented cancer cells from entering mitosis. CBLC deficiency significantly delayed cell cycle progression, reduced the mitotic population, and increased apoptosis of LAD cells. Targeting CBLC inhibited tumor growth of LAD cells and enhanced their sensitivity to paclitaxel in xenograft models. Immunohistochemical staining of the tissue microarray also revealed a positive correlation between the expression of CBLC and AURKA in normal and LAD tissues, further supporting the positive regulation of AURKA expression by CBLC. In summary, these findings indicate that the oncogenic E3 ligase CBLC plays a role in mitotic entry by stabilizing AURKA via ubiquitination in LAD. This work demonstrates that targeting CBLC combined with paclitaxel might be a potential option for the treatment of LAD patients who have no available targeted therapies.

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Fig. 1: CBLC is a novel binding partner of Aurora kinases.
Fig. 2: CBLC binds and ubiquitinates AURKA.
Fig. 3: CBLC positively regulates protein stability of AURKA.
Fig. 4: CBLC deficiency inhibited mitotic entry, promoted apoptotic death and suppressed malignant pathways by downregulating AURKA.
Fig. 5: The effect of CBLC expression on tumor growth and paclitaxel sensitivity of LAD.
Fig. 6: Correlation of CBLC and AURKA expression in normal and LAD tissues.

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Acknowledgements

This work was supported by the Ministry of Science and Technology of Taiwan (MOST 109-2314-B-567-001-MY2 and MOST 110-2314-B-567-004 to SYH, MOST 109-2320-B-A49-001 to CWW) and Cardinal Tien Hospital (CTH 110A-2207 to SYH and CTH 110A-NDMC-2227 to CYW). We also thank the core facilities of IBMS, funded by Academia Sinica Core Facility and Innovative Instrument Projects (AS-CFII-108-115, AS-CFII-108-113).

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  1. These authors contributed equally: Yi-Chun Lu, Shih-Hsin Hsiao.

Authors and Affiliations

  1. Medical Research Center, Cardinal Tien Hospital, New Taipei, Taiwan

    Shiao-Ya Hong & Yi-Chun Lu

  2. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    Shiao-Ya Hong, Yu-Rung Kao & Cheng-Wen Wu

  3. Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan

    Shih-Hsin Hsiao

  4. Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Meng-Hsuan Lee & Yi-Ping Lin

  5. Department of Internal Medicine, Cardinal Tien Hospital, New Taipei, Taiwan

    Cheng-Yi Wang

  6. School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei, Taiwan

    Cheng-Yi Wang

  7. Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Cheng-Wen Wu

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Contributions

SYH, SHH, CYW, and CWW conceived the project. SYH, YCL, YRK, MHL, and YPL designed and performed the experiments. All authors analyzed and interpreted the data. SYH, SHH, CYW, and CWW drafted the paper.

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Correspondence to Cheng-Yi Wang or Cheng-Wen Wu.

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Hong, SY., Lu, YC., Hsiao, SH. et al. Stabilization of AURKA by the E3 ubiquitin ligase CBLC in lung adenocarcinoma. Oncogene 41, 1907–1917 (2022). https://doi.org/10.1038/s41388-022-02180-6

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