Identification of proteasomal catalytic subunit PSMA6 as a therapeutic target for lung cancer.
Identification of proteasomal catalytic subunit PSMA6 as a therapeutic target for lung cancer.
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DOI：
10.1111/cas.13185
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发表时间：
2017-04
期刊：
影响因子：
5.7
通讯作者：
Hasegawa Y
中科院分区：
文献类型：
--
作者：
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
为了确定肺癌的潜在治疗靶点，我们结合全基因组表达和拷贝数数据进行了半全基因组shRNA筛选。shRNA筛选NCI‐H460中5043个基因，筛选出51个候选基因。途径分析结果显示，51个基因富集于核糖体、蛋白酶体、RNA聚合酶、嘧啶代谢和剪接体5条途径。我们专注于涉及六个候选基因的蛋白酶体途径，因为它的激活已在包括肺癌在内的多种人类恶性肿瘤中得到证实。微阵列表达和阵列CGH数据显示，20S催化核心复合物的蛋白酶体亚基PSMA6在肺癌细胞系中高表达，在某些情况下出现复发性基因扩增。因此，我们进一步研究了PSMA6在肺癌中的作用。在癌细胞系中，沉默PSMA6诱导凋亡或G2/M细胞周期阻滞，但在永生化正常肺细胞系中没有。这些结果表明，PSMA6是一个具有高治疗指数的有吸引力的肺癌靶点。
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.