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Xin-Chun Zhao



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    MA21 - Molecular Subtyping, CBL3, and Non Coding RNA (ID 924)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 205 BD
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      MA21.02 - Identification of an E2 Ubiquitin Conjugase CDC34 That Competes With E3 Ligase c-Cbl to Stabilize EGFR and Promotes Lung Carcinogenesis (ID 12416)

      15:20 - 15:25  |  Author(s): Xin-Chun Zhao

      • Abstract
      • Presentation
      • Slides

      Background

      The ubiquitin (Ub)-proteasome system (UPS) is the principal pathway for diverse intracellular protein degradation, in which the E2 ubiquitin-conjugating enzymes play critical roles by transferring the Ub on their conserved cysteine residue to the ε-amino group of lysine residues on substrates.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To systematically identify ubiquitin pathway genes that are critical to lung carcinogenesis, we used a highthrough-put silencing method to knockdown 696 genes in non-small cell lung cancer (NSCLC) cells, and investigated the significance of the candidates in patient samples, cellular and animal models.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified 31 candidates that were required for cell proliferation in two NSCLC lines, among which the E2 ubiquitin conjugase CDC34
      represented the most significant one. CDC34 was elevated in tumor tissues in 67 of 102 (65.7%) NSCLCs, and smokers had higher CDC34 than nonsmokers. The expression of CDC34 was inversely associated with overall survival of the patients. Forced expression of CDC34 promoted, whereas knockdown of CDC34 inhibited lung cancer in vitro and in vivo. CDC34 bound EGFR and competed with E3 ligase c-Cbl to inhibit the polyubiquitination and subsequent degradation of EGFR. In EGFR-L858R and EGFR-T790M/Del(exon 19)-driven lung cancer in mice, nockdown of CDC34 by lentivirus mediated transfection of short hairpin RNA significantly inhibited tumor formation.

      8eea62084ca7e541d918e823422bd82e Conclusion

      These results demonstrate that an E2 enzyme is capable of competing with E3 ligase to inhibit ubiquitination and subsequent degradation of oncoprotein substrate, and CDC34 represents an attractive therapeutic target for NSCLCs with or without drug-resistant EGFR mutations.

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