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Updated: Dec 27, 2025
Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
Published on: October 5, 2020
Systematic identification of CDC34 that functions to stabilize EGFR and promote lung carcinogenesis
Xin-Chun Zhao1, Gui-Zhen Wang2, Zhe-Sheng Wen3
1State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, China; Cancer Institute, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China.
Background:
How the oncoprotein epidermal growth factor receptor (EGFR) evades proteolytic degradation and accumulates in non-small cell lung cancer (NSCLC) remains unclear, and ubiquitin pathway genes (UPGs) that are critical to NSCLC needs to be systematically identified.
Methods:
A total of 696 UPGs (including E1, E2, E3, and deubiquitinases) were silenced by small interfering RNA (siRNA) library in NSCLC cells, the candidates were verified, and their significance was evaluated in patients with NSCLC. The effects of a candidate gene on EGFR were investigated in vitro and in vivo.
Findings:
We report 31 candidates that are required for cell proliferation, with the E2 ubiquitin conjugase CDC34 as the most significant one. CDC34 is elevated in tumor tissues in 76 of 114 (66.7%) NSCLCs and inversely associated with prognosis, is higher in smoker patients than nonsmoker patients, and is induced by tobacco carcinogens in normal human lung epithelial cells. Forced expression of CDC34 promotes, whereas knockdown of CDC34 inhibits, NSCLC cell proliferation in vitro and in vivo. CDC34 competes with c-Cbl to bind Y1045 to inhibit polyubiquitination and degradation of EGFR. In EGFR-L858R and EGFR-T790M/Del (exon 19)-driven lung tumor growth in mouse models, knockdown of CDC34 significantly inhibits tumor formation.
Interpretation:
These results demonstrate that an E2 enzyme is capable of competing with E3 ligase to stabilize substrates, and CDC34 represents an attractive therapeutic target for NSCLCs.
Funding:
National Key Research and Development Program of China, National Natural Science Foundation of China, and the CAMS Innovation Fund for Medical Sciences.
Insights
The E2 enzyme CDC34 promotes non-small cell lung cancer (NSCLC) growth by preventing epidermal growth factor receptor (EGFR) degradation. Targeting CDC34 offers a promising therapeutic strategy for NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The mechanism by which epidermal growth factor receptor (EGFR) evades degradation in non-small cell lung cancer (NSCLC) is not fully understood.
- Systematic identification of ubiquitin pathway genes (UPGs) crucial for NSCLC is needed.
Purpose of the Study:
- To identify critical ubiquitin pathway genes involved in NSCLC progression.
- To investigate the role of identified genes in regulating EGFR stability and NSCLC cell proliferation.
Main Methods:
- Screening of 696 UPGs using small interfering RNA (siRNA) in NSCLC cells.
- In vitro and in vivo validation of candidate genes, including CDC34.
- Analysis of CDC34 expression and its association with patient prognosis and smoking status.
Main Results:
- 31 UPGs essential for NSCLC cell proliferation were identified, with E2 ubiquitin conjugase CDC34 being the most significant.
- CDC34 is upregulated in 66.7% of NSCLC tumors, inversely correlated with prognosis, and induced by tobacco carcinogens.
- CDC34 knockdown inhibits NSCLC proliferation and tumor growth by preventing EGFR degradation, while its overexpression promotes it.
Conclusions:
- The E2 enzyme CDC34 competes with E3 ligases to stabilize substrates like EGFR.
- CDC34 is a potential therapeutic target for non-small cell lung cancer.
