Identification of curcumin as a novel natural inhibitor of rDNA transcription
Identification of curcumin as a novel natural inhibitor of rDNA transcription
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鉴定姜黄素为新型 rDNA 转录天然抑制剂
DOI：
10.1080/15384101.2020.1843817
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发表时间：
2020-11-11
期刊：
影响因子：
4.3
通讯作者：
Wan, Wei
中科院分区：
文献类型：
--
作者：
Xu, Yinfeng;Wu, Yaosen;Wan, Wei
核糖体DNA （rDNA）转录通过产物核糖体RNA （rRNA）驱动细胞生长和细胞增殖，rRNA是核糖体的重要组成部分。鉴于rRNA在核糖体生物发生中的基本作用，rDNA转录已成为包括各种类型癌症在内的许多人类疾病的有效靶点之一。在这项研究中，我们发现姜黄素，一种古老的药物，作为一种新的天然rDNA转录抑制剂。姜黄素处理破坏rDNA启动子处RNA聚合酶I预起始复合物的组装，抑制rDNA启动子活性，导致rRNA合成减少。此外，姜黄素处理刺激自噬体的形成，促进细胞的自噬降解。从机制上讲，姜黄素通过抑制mTOR溶酶体定位，使rDNA转录和自噬诱导的上游调节剂雷帕霉素复合物1 （mTORC1）失活。功能上，姜黄素处理抑制蛋白质合成、细胞生长和细胞增殖。综上所述，这些发现确定了姜黄素是一种有效的rDNA转录抑制剂，并为姜黄素的抗癌特性提供了新的机制。缩写：Atg：自噬相关；GFP：绿色荧光蛋白；LAMP2：溶酶体相关膜蛋白2；LC3：微管相关蛋白1轻链3；MEF：小鼠胚胎成纤维细胞；mTORC1：雷帕霉素复合物1的机制靶点rDNA：核糖体DNA；rRNA：核糖体RNA；TP53INP2：肿瘤蛋白p53诱导核蛋白2。
ABSTRACT Ribosomal DNA (rDNA) transcription drives cell growth and cell proliferation via the product ribosomal RNA (rRNA), the essential component of ribosome. Given the fundamental role of rRNA in ribosome biogenesis, rDNA transcription has emerged as one of the effective targets for a number of human diseases including various types of cancers. In this study, we identify curcumin, an ancient drug, as a novel natural inhibitor of rDNA transcription. Curcumin treatment impairs the assembly of the RNA polymerase I preinitiation complex at rDNA promoters and represses rDNA promoter activity, which leads to the decrease of rRNA synthesis. In addition, curcumin treatment stimulates autophagosome formation and promotes autophagic degradation in cells. Mechanistically, curcumin inactivates the mechanistic target of rapamycin complex 1 (mTORC1), the upstream regulator of rDNA transcription and autophagy induction, by inhibiting mTOR lysosomal localization. Functionally, curcumin treatment inhibits protein synthesis, cell growth and cell proliferation. Taken together, these findings identify curcumin as an effective inhibitor of rDNA transcription and provide novel mechanisms for the anticancer properties of curcumin. Abbreviations: Atg: autophagy-related; GFP: green fluorescent protein; LAMP2: lysosomal associated membrane protein 2; LC3: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; mTORC1: mechanistic target of rapamycin complex 1; rDNA: ribosomal DNA; rRNA: ribosomal RNA; TP53INP2: tumor protein p53 inducible nuclear protein 2.