Identification of proteasomal catalytic subunit PSMA6 as a therapeutic target for lung cancer. Issue 4 (25th April 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Cancer science. Volume 108:Issue 4(2017)
• Page Start: 732
• Page End: 743
• Publication Date: 2017-04-25
• Subjects: Apoptosis -- lung neoplasms -- proteasome endopeptidase complex -- small interfering RNA -- spliceosomes; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.13185
• Languages: English
• ISSNs: 1347-9032

Abstract

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. Abstract : By doing an integrative analysis we have identified PSMA6, a subunit of the proteasome complex, as one of the most promising targets for lung cancer. We showed that PSMA6 knockdown suppressed the viability of cancer cells through the induction of apoptosis or cell cycle arrest at G2/M, with only a minimal effect on normal lung epithelial cells. Our data suggested that targeting PSMA6 for lung cancer may be an attractive novel therapeutic strategy.