Identification of proteasomal catalytic subunit PSMA6 as a therapeutic target for lung cancer

Tomohiko Kakumu, Mitsuo Sato, Daiki Goto, Toshio Kato, Naoyuki Yogo, Tetsunari Hase, Masahiro Morise, Takayuki Fukui, Kohei Yokoi, 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

2 Citations (Scopus)

Abstract

To identify potential therapeutic targets for lung cancer, we performed semi-genome-wide shRNA screening combined with the utilization of genome-wide expression and copy number data. shRNA screening targeting 5043 genes in NCI-H460 identified 51 genes as candidates. Pathway analysis revealed that the 51 genes were enriched for the five pathways, including ribosome, proteasome, RNA polymerase, pyrimidine metabolism and spliceosome pathways. We focused on the proteasome pathway that involved six candidate genes because its activation has been demonstrated in diverse human malignancies, including lung cancer. Microarray expression and array CGH data showed that PSMA6, a proteasomal subunit of a 20S catalytic core complex, was highly expressed in lung cancer cell lines, with recurrent gene amplifications in some cases. Therefore, we further examined the roles of PSMA6 in lung cancer. Silencing of PSMA6 induced apoptosis or G2/M cell cycle arrest in cancer cell lines but not in an immortalized normal lung cell line. These results suggested that PSMA6 serves as an attractive target with a high therapeutic index for lung cancer.

Original languageEnglish
Pages (from-to)732-743
Number of pages12
JournalCancer Science
Volume108
Issue number4
DOIs
Publication statusPublished - 01-04-2017

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Lung Neoplasms
Catalytic Domain
Proteasome Endopeptidase Complex
Cell Line
Small Interfering RNA
Genome
G2 Phase Cell Cycle Checkpoints
Spliceosomes
Genes
Therapeutics
Gene Targeting
Gene Amplification
DNA-Directed RNA Polymerases
Ribosomes
Neoplasms
Apoptosis
Lung

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kakumu, T., Sato, M., Goto, D., Kato, T., Yogo, N., Hase, T., ... Hasegawa, Y. (2017). Identification of proteasomal catalytic subunit PSMA6 as a therapeutic target for lung cancer. Cancer Science, 108(4), 732-743. https://doi.org/10.1111/cas.13185
Kakumu, Tomohiko ; Sato, Mitsuo ; Goto, Daiki ; Kato, Toshio ; Yogo, Naoyuki ; Hase, Tetsunari ; Morise, Masahiro ; Fukui, Takayuki ; Yokoi, Kohei ; Sekido, Yoshitaka ; Girard, Luc ; Minna, John D. ; Byers, Lauren A. ; Heymach, John V. ; Coombes, Kevin R. ; Kondo, Masashi ; Hasegawa, Yoshinori. / Identification of proteasomal catalytic subunit PSMA6 as a therapeutic target for lung cancer. In: Cancer Science. 2017 ; Vol. 108, No. 4. pp. 732-743.
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Kakumu, T, Sato, M, Goto, D, Kato, T, Yogo, N, Hase, T, Morise, M, Fukui, T, Yokoi, K, Sekido, Y, Girard, L, Minna, JD, Byers, LA, Heymach, JV, Coombes, KR, Kondo, M & Hasegawa, Y 2017, 'Identification of proteasomal catalytic subunit PSMA6 as a therapeutic target for lung cancer', Cancer Science, vol. 108, no. 4, pp. 732-743. https://doi.org/10.1111/cas.13185

Identification of proteasomal catalytic subunit PSMA6 as a therapeutic target for lung cancer. / Kakumu, Tomohiko; Sato, Mitsuo; Goto, Daiki; Kato, Toshio; Yogo, Naoyuki; Hase, Tetsunari; Morise, Masahiro; Fukui, Takayuki; Yokoi, Kohei; Sekido, Yoshitaka; Girard, Luc; Minna, John D.; Byers, Lauren A.; Heymach, John V.; Coombes, Kevin R.; Kondo, Masashi; Hasegawa, Yoshinori.

In: Cancer Science, Vol. 108, No. 4, 01.04.2017, p. 732-743.

Research output: Contribution to journalArticle

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T1 - Identification of proteasomal catalytic subunit PSMA6 as a therapeutic target for lung cancer

AU - Kakumu, Tomohiko

AU - Sato, Mitsuo

AU - Goto, Daiki

AU - Kato, Toshio

AU - Yogo, Naoyuki

AU - Hase, Tetsunari

AU - Morise, Masahiro

AU - Fukui, Takayuki

AU - Yokoi, Kohei

AU - Sekido, Yoshitaka

AU - Girard, Luc

AU - Minna, John D.

AU - Byers, Lauren A.

AU - Heymach, John V.

AU - Coombes, Kevin R.

AU - Kondo, Masashi

AU - Hasegawa, Yoshinori

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N2 - To identify potential therapeutic targets for lung cancer, we performed semi-genome-wide shRNA screening combined with the utilization of genome-wide expression and copy number data. shRNA screening targeting 5043 genes in NCI-H460 identified 51 genes as candidates. Pathway analysis revealed that the 51 genes were enriched for the five pathways, including ribosome, proteasome, RNA polymerase, pyrimidine metabolism and spliceosome pathways. We focused on the proteasome pathway that involved six candidate genes because its activation has been demonstrated in diverse human malignancies, including lung cancer. Microarray expression and array CGH data showed that PSMA6, a proteasomal subunit of a 20S catalytic core complex, was highly expressed in lung cancer cell lines, with recurrent gene amplifications in some cases. Therefore, we further examined the roles of PSMA6 in lung cancer. Silencing of PSMA6 induced apoptosis or G2/M cell cycle arrest in cancer cell lines but not in an immortalized normal lung cell line. These results suggested that PSMA6 serves as an attractive target with a high therapeutic index for lung cancer.

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