Systematic Identification of CDC34 that Functions to Stabilize EGFR and Promote Lung Carcinogenesis

Abstract

To identify ubiquitin pathway genes (UPGs) that are critical to lung carcinogenesis, 696 UPGs were knocked down in non-small cell lung cancer (NSCLC) cells. 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 67 of 102 (65.7%) NSCLCs and inversely associated with prognosis, is higher in smokers than nonsmokers, and is induced by tobacco carcinogens in normal human lung epithelial cells. In vitro and in vivo, overexpression of CDC34 promotes NSCLC cell proliferation, whereas knockdown of CDC34 inhibits proliferation. CDC34 competes with c-Cbl to bind Y1045 to inhibit polyubiquitination and degradation of EGFR and attenuates EGFR dephosphorylation by promoting CDC25A catabolism. In EGFR-L858R and EGFR-T790M/Del (exon 19)-driven lung tumor growth in mouse models, knockdown of CDC34 significantly inhibits tumor formation. 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: This work was supported by the National Key Research and Development Program of China (2016YFC0905501), the National Natural Science Funds for Distinguished Young Scholar (81425025), the Key Project of the National Natural Science Foundation of China (81830093), the National Natural Science Foundation of China (81672765 and 81802796), and the CAMS Innovation Fund for Medical Sciences (CIFMS; No. 2019-I2M-1-003). Declaration of Interest: No potential conflicts of interest were disclosed. Ethical Approval: The study was approved by the local research ethics committees of all participating sites; all lung cancer samples were collected with informed consent. The animal studies were approved by the Institutional Review Board of Institute of Zoology, Chinese Academy of Sciences, and the methods were carried out in accordance with the approved guidelines.