Long noncoding RNAs and sulforaphane: a target for chemoprevention and suppression of prostate cancer.
Long noncoding RNAs and sulforaphane: a target for chemoprevention and suppression of prostate cancer.
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DOI：
10.1016/j.jnutbio.2017.01.001
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
Ho E
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作者：
Beaver LM;Kuintzle R;Buchanan A;Wiley MW;Glasser ST;Wong CP;Johnson GS;Chang JH;Löhr CV;Williams DE;Dashwood RH;Hendrix DA;Ho E
长链非编码RNA（lncRNA）在癌症的发生和发展中起着重要作用。饮食对lncRNA表达的影响在很大程度上是未知的。萝卜硫素（SFN），从西兰花等蔬菜中获得，可以预防和抑制癌症的形成。在这里，我们测试了SFN减弱癌症相关lncRNA表达的假设。我们分析了用15 μM SFN或DMSO处理的正常人前列腺上皮细胞和前列腺癌细胞的全基因组RNA测序数据。SFN显著改变了每种细胞类型中约100种lncRNA的表达，并使癌细胞中差异表达的一些lncRNA的表达正常化。SFN介导的lncRNA表达的改变与调节细胞周期、信号转导和代谢的基因相关。LINC 01116在功能上进行了研究，因为它在几种癌症中过表达，并在SFN治疗后被转录抑制。用siRNA敲低LINC 01116降低了前列腺癌细胞的增殖，并显著上调了几个基因，包括GAPDH（调节糖酵解），MAP 1 LC 3B 2（自噬）和H2 AFY（染色质结构）。当通过CRISPR/CAS 9方法破坏LINC 01116基因时，发现癌细胞形成集落的能力降低4倍，进一步支持LINC 01116在PC-3细胞中的致癌功能。我们鉴定了LINC 01116的一种新亚型，并从生物信息学角度研究了LINC 01116通过ssRNA：dsDNA三链体与靶基因相互作用的可能性。我们的数据显示，饮食中的化学物质可以影响功能重要的lncRNA的表达，并提出了SFN可以预防和抑制前列腺癌的新机制。
Long non-coding RNAs (lncRNAs) have emerged as important in cancer development and progression. The impact of diet on lncRNA expression is largely unknown. Sulforaphane (SFN), obtained from vegetables like broccoli, can prevent and suppress cancer formation. Here we tested the hypothesis that SFN attenuates the expression of cancer-associated lncRNAs. We analyzed whole genome RNA-sequencing data of normal human prostate epithelial cells and prostate cancer cells treated with 15 μM SFN or DMSO. SFN significantly altered expression of ~100 lncRNAs in each cell type, and normalized the expression of some lncRNAs that were differentially expressed in cancer cells. SFN-mediated alterations in lncRNA expression correlated with genes that regulate cell cycle, signal transduction, and metabolism. LINC01116 was functionally investigated because it was overexpressed in several cancers, and was transcriptionally repressed after SFN treatment. Knockdown of LINC01116 with siRNA decreased proliferation of prostate cancer cells, and significantly upregulated several genes including GAPDH (regulates glycolysis), MAP1LC3B2 (autophagy) and H2AFY (chromatin structure). A 4-fold decrease in the ability of the cancer cells to form colonies was found when the LINC01116 gene was disrupted through a CRISPR/CAS9 method, further supporting an oncogenic function for LINC01116 in PC-3 cells.. We identified a novel isoform of LINC01116 and bioinformatically investigated the possibility that LINC01116 could interact with target genes via ssRNA:dsDNA triplexes. Our data reveal that chemicals from the diet can influence the expression of functionally important lncRNAs, and suggest a novel mechanism by which SFN may prevent and suppress prostate cancer.