Dihydrotanshinone-I interferes with the RNA-binding activity of HuR affecting its post-transcriptional function.
Dihydrotanshinone-I interferes with the RNA-binding activity of HuR affecting its post-transcriptional function.
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DOI：
10.1038/srep16478
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发表时间：
2015-11-10
影响因子：
4.6
通讯作者：
Provenzani A
中科院分区：
文献类型：
--
作者：
D'Agostino VG;Lal P;Mantelli B;Tiedje C;Zucal C;Thongon N;Gaestel M;Latorre E;Marinelli L;Seneci P;Amadio M;Provenzani A
转录后调控是生理和病理条件下基因表达程序的重要决定因素。HUR是一种RNA结合蛋白，协调mRNAs的稳定和翻译，在炎症和肿瘤进展中起关键作用，包括肿瘤坏死因子-α(TNF)。我们通过对一组抗炎药进行高通量筛选，确定了低分子化合物15，16-二氢丹参酮-I(DHTS)，该化合物在中医药实践中广为人知，以防止HUR：RNA复合体的形成。我们发现DHTS在体外干扰了HUR与核糖核酸的结合步骤，其平衡解离常数在纳摩尔范围内(Ki = 3.74 ± 1.63 nM)。在乳腺癌细胞系中，短期暴露于DHTS以一种Hur依赖的方式影响TNF的mRNA稳定性和翻译效率，以及其转录后控制的其他功能读数，如选定的前mRNAs的稳定性。重要的是，我们发现乳腺癌细胞对DHTS的迁移和敏感性受到Hur表达的调节，这表明Hur是DHTS的细胞内首选靶点之一。在这里，我们揭示了DHTS以前未知的分子机制，为从治疗上靶向Hur介导的炎症和癌细胞转录后控制开辟了新的视角。
Post-transcriptional regulation is an essential determinant of gene expression programs in physiological and pathological conditions. HuR is a RNA-binding protein that orchestrates the stabilization and translation of mRNAs, critical in inflammation and tumor progression, including tumor necrosis factor-alpha (TNF). We identified the low molecular weight compound 15,16-dihydrotanshinone-I (DHTS), well known in traditional Chinese medicine practice, through a validated high throughput screening on a set of anti-inflammatory agents for its ability to prevent HuR:RNA complex formation. We found that DHTS interferes with the association step between HuR and the RNA with an equilibrium dissociation constant in the nanomolar range in vitro (Ki = 3.74 ± 1.63 nM). In breast cancer cell lines, short term exposure to DHTS influences mRNA stability and translational efficiency of TNF in a HuR-dependent manner and also other functional readouts of its post-transcriptional control, such as the stability of selected pre-mRNAs. Importantly, we show that migration and sensitivity of breast cancer cells to DHTS are modulated by HuR expression, indicating that HuR is among the preferential intracellular targets of DHTS. Here, we disclose a previously unrecognized molecular mechanism exerted by DHTS, opening new perspectives to therapeutically target the HuR mediated, post-transcriptional control in inflammation and cancer cells.