RT Journal Article
SR Electronic
T1 Genome-wide identification of CDC34 that stabilizes EGFR and promotes lung carcinogenesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 255844
DO 10.1101/255844
A1 Xin-Chun Zhao
A1 Gui-Zhen Wang
A1 Yong-Chun Zhou
A1 Liang Ma
A1 Jie Liu
A1 Chen Zhang
A1 Da-Lin Zhang
A1 San-Hui Gao
A1 Li-Wei Qu
A1 Bin Zhang
A1 Chang-Li Wang
A1 Yun-Chao Huang
A1 Liang Chen
A1 Guang-Biao Zhou
YR 2018
UL http://biorxiv.org/content/early/2018/01/29/255844.abstract
AB To systematically identify ubiquitin pathway genes that are critical to lung carcinogenesis, we used a genome-wide silencing method in this study to knockdown 696 genes in non-small cell lung cancer (NSCLC) cells. 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, knockdown of CDC34 by lentivirus mediated transfection of short hairpin RNA significantly inhibited tumor formation. 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.