2. Academic Validation
  3. CRL2KLHDC3 mediates p14ARF N-terminal ubiquitylation degradation to promote non-small cell lung carcinoma progression

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

  • Oncogene. 2022 May;41(22):3104-3117. doi: 10.1038/s41388-022-02318-6.
Yang Liu 1,  Yuewen Luo 2 3,  Shumei Yan 4,  Yi-Fan Lian 5,  Shiyu Wu 2,  Miao Xu 1,  Lin Feng 1,  Xu Zhang 2,  Rong Li 2,  Xiantao Zhang 2,  Qi-Sheng Feng 1,  Yi-Xin Zeng 6,  Hui Zhang 7
Affiliations

Affiliations

  • 1 Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, 510060, China.
  • 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.
  • 3 School of Medicine, Sun Yat-sen University, Guangzhou/Shenzhen, 510080, China.
  • 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.
  • 5 Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 6 Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, 510060, China. zengyx@sysucc.org.cn.
  • 7 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. zhangh92@mail.sysu.edu.cn.
PMID: 35468939 DOI: 10.1038/s41388-022-02318-6
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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