Gene amplification of the histone methyltransferase SETDB1 contributes to human lung tumorigenesis.
Gene amplification of the histone methyltransferase SETDB1 contributes to human lung tumorigenesis.
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组蛋白修饰模式的破坏是人类肿瘤最常见的特征之一。然而，很少有组蛋白修饰基因的遗传改变已被描述在肿瘤发生。在此，我们发现组蛋白甲基转移酶SETDB1在非小和小肺癌细胞系和原发性肿瘤中经历基因扩增。在这些转化细胞中存在额外的SETDB 1基因拷贝与相应mRNA和蛋白质的较高水平相关。从功能的角度来看，扩增细胞中SETDB 1表达的缺失减少了细胞培养和裸鼠模型中的癌症生长，而其过表达增加了肿瘤侵袭性。SETDB 1基因剂量的增加也与对SETDB 1干扰药物光神霉素介导的生长抑制作用的敏感性增强有关。总的来说，研究结果确定SETDB 1是一个真正的癌基因，在肺癌中经历基因扩增相关的激活，并表明它有可能成为新的治疗策略。
Disruption of the histone modification patterns is one of the most common features of human tumors. However, few genetic alterations in the histone modifier genes have been described in tumorigenesis. Herein we show that the histone methyltransferase SETDB1 undergoes gene amplification in non-small and small lung cancer cell lines and primary tumors. The existence of additional copies of the SETDB1 gene in these transformed cells is associated with higher levels of the corresponding mRNA and protein. From a functional standpoint, the depletion of SETDB1 expression in amplified cells reduces cancer growth in cell culture and nude mice models, whereas its overexpression increases the tumor invasiveness. The increased gene dosage of SETDB1 is also associated with enhanced sensitivity to the growth inhibitory effect mediated by the SETDB1-interfering drug mithramycin. Overall, the findings identify SETDB1 as a bona fide oncogene undergoing gene amplification-associated activation in lung cancer and suggest its potential for new therapeutic strategies.
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影响因子：
7.3
作者：
Goeze, A;Schlüns, K;Petersen, I
通讯作者：
Petersen, I
影响因子：
--
作者：
Luk, C;Tsao, MS;Squire, JA
通讯作者：
Squire, JA
影响因子：
8.8
作者：
Canaani, E;Nakamura, T;Rozovskaia, T;Smith, S T;Mori, T;Croce, C M;Mazo, A
通讯作者：
Mazo, A
影响因子：
4.8
作者：
Cho, Sunwha;Park, Jung Sun;Kang, Yong-Kook
通讯作者：
Kang, Yong-Kook
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS