Food-Derived Compounds Apigenin and Luteolin Modulate mRNA Splicing of Introns with Weak Splice Sites
Food-Derived Compounds Apigenin and Luteolin Modulate mRNA Splicing of Introns with Weak Splice Sites
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DOI：
10.1016/j.isci.2019.11.033
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发表时间：
2019-12-20
期刊：
影响因子：
5.8
通讯作者：
Masuda, Seiji
中科院分区：
文献类型：
--
作者：
Kurata, Masashi;Fujiwara, Naoko;Masuda, Seiji
癌细胞通常对剪接抑制剂表现出极端敏感性。我们确定了食物来源的黄酮类化合物，芹菜素和毛地黄黄酮，作为在全基因组水平上调节mRNA剪接的化合物，然后抑制增殖。它们与mRNA剪接相关蛋白结合，诱导处理细胞中剪接模式的广泛变化。它们对剪接的抑制活性相对适中，具有弱剪接位点的内含子往往对它们敏感。这样的内含子保持未剪接，并且所产生的含有内含子的mRNA保留在细胞核中，导致poly（A）（+）RNA在这些类黄酮处理的细胞中的核积累。致瘤细胞比非致瘤细胞对这些黄酮类化合物更敏感，无论是核聚（A）（+）RNA积累表型还是细胞活力。这项研究说明了这些黄酮类化合物抑制体内肿瘤进展的可能机制，这些机制已被先前的研究所证实，并提供了每日摄入适度剪接抑制剂以预防癌症发展的潜力。
Cancer cells often exhibit extreme sensitivity to splicing inhibitors. We identified food-derived flavonoids, apigenin and luteolin, as compounds that modulate mRNA splicing at the genome-wide level, followed by proliferation inhibition. They bind to mRNA splicing-related proteins to induce a wide-spread change of splicing patterns in treated cells. Their inhibitory activity on splicing is relatively moderate, and introns with weak splice sites tend to be sensitive to them. Such introns remain unspliced, and the resulting intron-containing mRNAs are retained in the nucleus, resulting in the nuclear accumulation of poly(A)(+) RNAs in these flavonoid-treated cells. Tumorigenic cells aremore susceptible to these flavonoids than nontumorigenic cells, both for the nuclear poly(A)(+) RNA-accumulating pheno-type and cell viability. This study illustrates the possible mechanism of these flavonoids to suppress tumor progression in vivo that were demonstrated by previous studies and provides the potential of daily intake of moderate splicing inhibitors to prevent cancer development.