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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalCancer Science
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Eukaryotic Initiation Factor-2
Peptide Initiation Factors
Non-Small Cell Lung Carcinoma
Lung Neoplasms
Small Interfering RNA
Cell Line
Genes
Genome
G1 Phase Cell Cycle Checkpoints
Heterotrimeric GTP-Binding Proteins
Gene Dosage
Gene Targeting
Atlases
Therapeutics
RNA Interference
Transcription Factors
Epithelial Cells
Databases
Gene Expression
Lung

Keywords

  • Adenocarcinoma
  • Eukaryotic initiation factor-2
  • G1 phase cell cycle checkpoints
  • Heterotrimeric GTP-binding proteins
  • RNA interference

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

eIF2β, a subunit of translation-initiation factor EIF2, is a potential therapeutic target for non-small cell lung cancer. / Tanaka, Ichidai; Sato, Mitsuo; Kato, Toshio; Goto, Daiki; Kakumu, Tomohiko; Miyazawa, Ayako; Yogo, Naoyuki; Hase, Tetsunari; Morise, Masahiro; Sekido, Yoshitaka; Girard, Luc; Minna, John D.; Byers, Lauren A.; Heymach, John V.; Coombes, Kevin R.; Kondo, Masashi; Hasegawa, Yoshinori.

In: Cancer Science, 01.01.2018.

Research output: Contribution to journalArticle

Tanaka, I, Sato, M, Kato, T, Goto, D, Kakumu, T, Miyazawa, A, Yogo, N, Hase, T, Morise, M, Sekido, Y, Girard, L, Minna, JD, Byers, LA, Heymach, JV, Coombes, KR, Kondo, M & Hasegawa, Y 2018, 'eIF2β, a subunit of translation-initiation factor EIF2, is a potential therapeutic target for non-small cell lung cancer', Cancer Science. https://doi.org/10.1111/cas.13602
Tanaka, Ichidai ; Sato, Mitsuo ; Kato, Toshio ; Goto, Daiki ; Kakumu, Tomohiko ; Miyazawa, Ayako ; Yogo, Naoyuki ; Hase, Tetsunari ; Morise, Masahiro ; Sekido, Yoshitaka ; Girard, Luc ; Minna, John D. ; Byers, Lauren A. ; Heymach, John V. ; Coombes, Kevin R. ; Kondo, Masashi ; Hasegawa, Yoshinori. / eIF2β, a subunit of translation-initiation factor EIF2, is a potential therapeutic target for non-small cell lung cancer. In: Cancer Science. 2018.
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abstract = "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.",
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AU - Hase, Tetsunari

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AU - Sekido, Yoshitaka

AU - Girard, Luc

AU - Minna, John D.

AU - Byers, Lauren A.

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AU - Coombes, Kevin R.

AU - Kondo, Masashi

AU - Hasegawa, Yoshinori

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