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CRL2KLHDC3 mediates p14ARF N-terminal ubiquitylation degradation to promote non-small cell lung carcinoma progression

Oncogene volume 41, pages 3104–3117 (2022)Cite this article

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Abstract

Kelch superfamily involves a variety of proteins containing multiple kelch motif and is well characterized as substrate adaptors for CUL3 E3 ligases, which play critical roles in carcinogenesis. However, the role of kelch proteins in lung cancer remains largely unknown. In this study, the non-small cell lung cancer (NSCLC) patients with higher expression of a kelch protein, kelch domain containing 3 (KLHDC3), showed worse overall survival. KLHDC3 deficiency affected NSCLC cell lines proliferation in vitro and in vivo. Further study indicated that KLHDC3 mediated CUL2 E3 ligase and tumor suppressor p14ARF interaction, facilitating the N-terminal ubiquitylation and subsequent degradation of p14ARF. Interestingly, Gefitinib-resistant NSCLC cell lines displayed higher KLHDC3 protein levels. Gefitinib and Osimertinib medications were capable of upregulating KLHDC3 expression to promote p14ARF degradation in the NSCLC cell lines. KLHDC3 shortage significantly increased the sensitivity of lung cancer cells to epidermal growth factor receptor (EGFR)-targeted drugs, providing an alternative explanation for the development of Gefitinib and Osimertinib resistance in NSCLC therapy. Our works suggest that CRL2KLHDC3 could be a valuable target to regulate the abundance of p14ARF and postpone the occurrence of EGFR-targeted drugs resistance.

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Fig. 1: KLHDC3 is highly expressed in NSCLC.
Fig. 2: Elevated KLHDC3 expression correlates with poor prognosis in NSCLC patients.
Fig. 3: KLHDC3 is required for NSCLC tumorigenesis.
Fig. 4: KLHDC3 mediates CUL2-p14ARF interaction.
Fig. 5: CUL2-KLHDC3 accelerates p14ARF degradation.
Fig. 6: KLHDC3 is a novel CUL2 E3 ubiquitin ligase adaptor of p14ARF.
Fig. 7: Gefitinib and Osimertinib upregulate KLHDC3 expression in NSCLC.

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Acknowledgements

We thank Dr Li Zhang for kindly providing lung cancer cell lines. This work was supported by the Special Reserach Program of Sun Yat-sen University Cancer Center to Y-XZ; the National Special Research Program of China for Important Infectious Diseases (2018ZX10302103 and 2017ZX10202102), the Important Key Program of NSFC (81730060), and the Joint-Innovation Program in Healthcare for Special Scientific Research Projects of Guangzhou (201803040002) to HZ; the Natural Science Foundation of Guangdong, China (Excellent Youth Foundation) and the Fundamental Research Funds for the Central Universities to MX.

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Authors and Affiliations

  1. Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, 510060, China

    Yang Liu, Miao Xu, Lin Feng, Qi-Sheng Feng & Yi-Xin Zeng

  2. Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China

    Yuewen Luo, Shiyu Wu, Xu Zhang, Rong Li, Xiantao Zhang & Hui Zhang

  3. School of Medicine, Sun Yat-sen University, Guangzhou/Shenzhen, 510080, China

    Yuewen Luo

  4. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China

    Shumei Yan

  5. Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Yi-Fan Lian

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Contributions

Conception and design: HZ, Y-XZ. Funding acquisition: HZ, Y-XZ, MX. Performed the experiments: YL, SMY, Y-FL, SW. Data analysis: YL, YWL, Y-FL, SMY, RL, XTZ. Administrative, technical, or material support: MX, XZ, LF, Q-SF. Writing and revision of the manuscript: YL, YWL, HZ, Y-XZ.

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Correspondence to Yi-Xin Zeng or Hui Zhang.

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Liu, Y., Luo, Y., Yan, S. et al. CRL2KLHDC3 mediates p14ARF N-terminal ubiquitylation degradation to promote non-small cell lung carcinoma progression. Oncogene 41, 3104–3117 (2022). https://doi.org/10.1038/s41388-022-02318-6

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