Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, Maryland, USA.
Nat Struct Mol Biol. 2010 Dec;17(12):1406-13. doi: 10.1038/nsmb.1941. Epub 2010 Nov 21.
Though the linkages between germline mutations of BRCA1 and hereditary breast cancer are well known, recent evidence suggests that altered BRCA1 transcription may also contribute to sporadic forms of breast cancer. Here we show that BRCA1 expression is controlled by a dynamic equilibrium between transcriptional coactivators and co-repressors that govern histone acetylation and DNA accessibility at the BRCA1 promoter. Eviction of the transcriptional co-repressor and metabolic sensor, C terminal-binding protein (CtBP), has a central role in this regulation. Loss of CtBP from the BRCA1 promoter through estrogen induction, depletion by RNA interference or increased NAD+/NADH ratio leads to HDAC1 dismissal, elevated histone acetylation and increased BRCA1 transcription. The active control of chromatin marks, DNA accessibility and gene expression at the BRCA1 promoter by this 'metabolic switch' provides an important molecular link between caloric intake and tumor suppressor expression in mammary cells.
虽然 BRCA1 种系突变与遗传性乳腺癌之间的联系是众所周知的，但最近的证据表明，BRCA1 转录的改变也可能导致散发性乳腺癌。在这里，我们表明 BRCA1 的表达受转录共激活因子和共抑制因子之间的动态平衡控制，这些因子调节 BRCA1 启动子处的组蛋白乙酰化和 DNA 可及性。转录共抑制因子和代谢传感器 C 端结合蛋白（CtBP）的驱逐在这种调节中起着核心作用。通过雌激素诱导、RNA 干扰耗竭或增加 NAD+/NADH 比值从 BRCA1 启动子中去除 CtBP，导致 HDAC1 被驱逐，组蛋白乙酰化增加，BRCA1 转录增加。这种“代谢开关”对 BRCA1 启动子上染色质标记、DNA 可及性和基因表达的主动控制，为哺乳动物细胞中热量摄入和肿瘤抑制因子表达之间提供了一个重要的分子联系。
