C/EBPα negatively regulates SIRT7 expression via recruiting HDAC3 to the upstream-promoter of hepatocellular carcinoma cells
C/EBPα negatively regulates SIRT7 expression via recruiting HDAC3 to the upstream-promoter of hepatocellular carcinoma cells
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DOI：
10.1016/j.bbagrm.2015.12.004
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发表时间：
2016-02-01
影响因子：
4.7
通讯作者：
Zhang, Ye
中科院分区：
文献类型：
--
作者：
Liu, Gui-fen;Lu, Jian-yi;Zhang, Ye
哺乳动物沉默信息调节因子2相关酶蛋白（SIRTs）是酵母Sir2的同源物，其特征为依赖烟酰胺腺嘌呤二核苷酸（NAD⁺）的Ⅲ类组蛋白去乙酰化酶。与在延长寿命中起直接作用的低等生物同类蛋白不同，哺乳动物SIRTs主要在代谢和细胞内稳态方面发挥作用，其中对SIRT7的了解最少。SIRT7定位于细胞核内，在与RNA聚合酶I相关的核仁中含量丰富，且与细胞增殖相关。相反，最近有研究表明SIRT7可特异性使染色质中的组蛋白H3赖氨酸18位点乙酰化（H3K18ac）去乙酰化，并且在大多数情况下抑制细胞增殖。尽管已有报道称微小RNA（如miR - 125b）可通过与SIRT7的3'非翻译区（3'UTR）结合而下调SIRT7，但SIRT7基因的调控机制仍不明确。在此，我们确定了人类SIRT7基因转录起始位点位于翻译密码子上游第23个A核苷酸处，且SIRT7是一个无TATA框和无起始子的基因。在所检测的三个物种中，- 256至 - 129 bp上游区域的序列具有相同的重要功能。我们发现了一个C / EBPα反应元件，该元件在体外可与C / EBPα和C / EBPβ结合。我们证明曲古抑菌素A（TSA）可诱导SIRT7基因转录，且在肝癌细胞中，只有组蛋白去乙酰化酶3（HDAC3），而非其缺失催化结构域的突变体，可与C / EBPα相互作用，占据C / EBPα元件并抑制SIRT7基因。据我们所知，这是关于SIRT7基因调控机制的首次报道，其中HDAC3与C / EBPα协同占据SIRT7基因上游区域的反应元件，从而抑制其在人类细胞中的表达。（C）2015爱思唯尔出版社。保留所有权利。
Mammalian Sirtuin proteins (SIRTs) are homologs of yeast Sir2, and characterized as class III histone deacetylases of NAD(+) dependence. Unlike their lower counterparts that are directly involved in the extending of lifespan, mammalian SIRTs mainly function in metabolism and cellular homeostasis, among them, SIRT7 is the least understood. SIRT7 is localized in the nucleus and rich in nucleoli associated with RNA polymerase I, and correlated with cell proliferation. In contrast, SIRT7 has recently been demonstrated to specifically deacetylate H3K18ac in the chromatin, and in most cases represses proliferation. Although MicroRNA as miR-125b has been reported to down -regulate SIRT7 by binding to its 3'UTR, however, how SIRT7 gene is regulated remains unclear. Here, we identified the transcription initiation site of human SIRT7 gene at the upstream 23rd A nucleotide respective to the translational codon, and the SIRT7 is a TATA-less and initiator -less gene. The sequences in the upstream region between -256 and -129 bp are identical with important functions in the three species detected. A C/EBP alpha responding element is found that binds both C/EBP alpha and C/EBP beta in vitro. We showed TSA induced SIRT7 gene transcription and only the HDAC3, but not its catalytic domain depleted mutant, interacted with C/EBP alpha to occupy the C/EBP alpha element and repressed SIRT7 gene in the hepatocellular carcinoma cells. To our knowledge, this is the first report on the regulation mechanism of SIRT7 gene, in which, HDAC3 collaborated with C/EBP alpha to occupy its responding element in the upstream region of SIRT7 gene and repressed its expression in human cells. (C) 2015 Elsevier B.V. All rights reserved.