NF-κB: Regulation by Methylation.
NF-κB: Regulation by Methylation.
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NF-κB：通过甲基化调节。
DOI：
10.1158/0008-5472.can-15-1022
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发表时间：
2015-09-15
期刊：
影响因子：
11.2
通讯作者：
Stark GR
中科院分区：
文献类型：
--
作者：
Lu T;Stark GR
在受到压力的正常细胞中，中央转录因子核因子 κB (NF-κB) 仅短暂激活，以调节下游免疫反应的激活。然而，在大多数癌症中，NF-κB 被异常激活，从而促进肿瘤发生和肿瘤进展。因此，下调NF-κB活性是癌症治疗的重要目标。为了在治疗上控制 NF-κB 活性，了解通常控制其激活的分子机制以及失调的 NF-κB 活性如何有助于疾病的发展是有帮助的。我们实验室和其他实验室的最新证据表明，除了之前观察到的 NF-κB 的各种翻译后修饰（包括磷酸化、泛素化和乙酰化）之外，NF-κB 还可以通过组蛋白修饰酶（包括赖氨酸和精氨酸甲基转移酶和去甲基化酶）在赖氨酸或精氨酸残基上可逆甲基化。此外，这些甲基化是激活许多下游基因所必需的。有趣的是，几种此类酶的扩增和突变与癌症有关。我们认为其中一些突变不仅可能改变组蛋白的甲基化，而且可能改变 NF-κB 的甲基化，使它们成为有吸引力的治疗靶点。
In normal cells exposed to stress, the central transcription factor nuclear factor κB (NF-κB) is activated only transiently, to modulate the activation of downstream immune responses. However, in most cancers, NF-κB is abnormally activated constitutively, contributing thus to oncogenesis and tumor progression. Therefore, down regulating NF-κB activity is an important goal of cancer treatment. In order to control NF-κB activity therapeutically, it is helpful to understand the molecular mechanisms that normally govern its activation, and how dysregulated NF-κB activity may aid the development of disease. Recent evidence from our labs and others indicates that, in addition to various post-translational modifications of NF-κB that have been observed previously, including phosphorylation, ubiquitination, and acetylation, NF-κB can be methylated reversibly on lysine or arginine residues by histone modifying enzymes, including lysine and arginine methyl transferases and demethylases. Furthermore, these methylations are required to activate many downstream genes. Interestingly, amplifications and mutations of several such enzymes have been linked to cancer. We propose that some of these mutations may alter the methylation not only of histones but also of NF-κB, making them attractive therapeutic targets.