Journal Article

eIF2β, a subunit of translation‐initiation factor EIF2, is a potential therapeutic target for non‐small cell lung cancer

Sato, Mitsuo, Miyazawa, Ayako, Coombes, Kevin R., Morise, Masahiro, Minna, John D., Goto, Daiki, Kakumu, Tomohiko, Kato, Toshio, Heymach, John V., Hasegawa, Yoshinori, Kondo, Masashi, Byers, Lauren A., Sekido, Yoshitaka, Girard, Luc, Yogo, Naoyuki, Hase, Tetsunari, Tanaka, Ichidai

2018

Overview

To identify novel therapeutic targets for non‐small cell lung cancer (NSCLC), we conducted an integrative study in the following 3 stages: (i) identification of potential target gene(s) through shRNA functional screens in 2 independent NSCLC cell lines; (ii) validation of the clinical relevance of identified gene(s) using public databases; and (iii) investigation of therapeutic potential of targeting the identified gene(s) in vitro. A semi‐genome‐wide shRNA screen was performed in NCI‐H358 cells, and was integrated with data from our previous screen in NCI‐H460 cells. Among genes identified in shRNA screens, 24 were present in both NCI‐H358 and NCI‐H460 cells and were considered potential targets. Among the genes, we focused on eIF2β, which is a subunit of heterotrimeric G protein EIF2 and functions as a transcription initiation factor. The eIF2β protein is highly expressed in lung cancer cell lines compared with normal bronchial epithelial cells, and gene copy number analyses revealed that eIF2β is amplified in a subset of NSCLC cell lines. Gene expression analysis using The Cancer Genome Atlas (TCGA) dataset revealed that eIF2β expression is significantly upregulated in lung cancer tissues compared with corresponding normal lung tissues. Furthermore, high eIF2β expression was correlated with poor survival in patients with lung adenocarcinoma, as shown in other cohorts using publicly available online tools. RNAi‐mediated depletion of eIF2β suppresses growth of lung cancer cells independently of p53 mutation status, in part through G1 cell cycle arrest. Our data suggest that eIF2β is a therapeutic target for lung cancer. Through semi‐genome wide shRNA screens using two lung cancer cell lines, we have identified the subunit eIF2β of translation‐initiation factor EIF2 as a potential therapeutic target for lung cancer. We show that eIF2β is highly expressed in lung cancer, in correlation with poor patient prognosis and that its knockdown induces G1 cell cycle arrest in lung cancer cell lines. These suggest therapeutic potential of targeting eIF2β for lung cancer.

• Publisher: John Wiley and Sons Inc
• Subject: A549 Cells / adenocarcinoma / Adenocarcinoma - drug therapy / Adenocarcinoma - genetics / Adenocarcinoma - metabolism / Aged / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - metabolism / Cell Line / Cell Line, Tumor / Eukaryotic Initiation Factor-2 - genetics / Eukaryotic Initiation Factor-2 - metabolism / eukaryotic initiation factor‐2 / Female / G1 phase cell cycle checkpoints / Gene Expression Regulation, Neoplastic / heterotrimeric GTP‐binding proteins / Humans / Kaplan-Meier Estimate / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Male / Middle Aged / Molecular Targeted Therapy / Original / Protein Subunits - genetics / Protein Subunits - metabolism / RNA Interference