The reversible epigenetic silencing of BRM: implications for clinical targeted therapy
The reversible epigenetic silencing of BRM: implications for clinical targeted therapy
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DOI：
10.1038/sj.onc.1210514
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发表时间：
2007-10-01
期刊：
影响因子：
8
通讯作者：
Reisman, D.
中科院分区：
文献类型：
--
作者：
Glaros, S.;Cirrincione, G. M.;Reisman, D.
SWI/SNF染色质重塑复合物充当指导和限制特定细胞程序（例如分化和生长控制）的执行的主开关。SWI/SNF功能需要两个旁系同源ATP酶亚基之一，Brahma（BRM）或BRM相关基因1（BRG 1），我们以前发现在癌细胞系和原发性肺癌中一起丢失。虽然已经发现BRG 1在癌细胞系中发生突变，但BRM沉默的潜在机制尚不清楚。为了解决这个问题，我们对10个BRM/BRG 10缺陷癌细胞系中的BRM进行了测序，发现BRM没有废除突变。此外，组蛋白去乙酰化酶（HDAC）抑制剂恢复BRM表达在这些BRG 1/BRM缺陷癌细胞系中的每一个，表明表观遗传沉默是一个主要的机制BRM表达的损失。尽管它们能够恢复BRM表达，但这些HDAC抑制剂在存在时也阻断BRM功能。然而，在它们被去除后，我们观察到BRM表达在几天内保持升高，并且在此期间，检测到BRM活性。我们还发现，BRM的抑制发生在广泛的人类肿瘤类型中，并且一个或两个BRM等位基因的缺失增强了小鼠肿瘤的发展。因此，BRG 1和BRM通过不同的机制沉默，并且可能在许多肿瘤类型中临床靶向和重新表达BRM，从而可能影响肿瘤的发展。
The SWI/SNF chromatin- remodeling complex serves as a master switch that directs and limits the execution of specific cellular programs, such as differentiation and growth control. SWI/SNF function requires one of two paralogous ATPase subunits, Brahma (BRM) or BRMrelated gene 1 (BRG1), which we previously found are lost together in cancer cell lines and primary lung cancers. Although BRG1 has been found to be mutated in cancer cell lines, the mechanisms underlying BRM silencing are not known. To address this question, we sequenced BRM in 10 BRM/BRG10 deficient cancer cell lines and found that BRM was devoid of abrogating mutations. Moreover, histone deacetylase (HDAC) inhibitors restored BRM expression in each of these BRG1/BRM-defficient cancer cell lines, indicating that epigenetic silencing is a major mechanism underlying the loss of BRM expression. Despite their ability restore BRM expression, these HDAC inhibitors also blocked BRM function when present. However, after their removal, we observed that BRM expression remained elevated for several days, and during this period, BRM activity was detected. We also found that the suppression of BRM occurs in a broad range of human tumor types and that loss of one or both BRM alleles potentiated tumor development in mice. Thus, BRG1 and BRM are silenced by different mechanisms, and it may be possible to clinically target and reexpress BRM in a number of tumor types, potentially impacting tumor development.