Stilbenoids remodel the DNA methylation patterns in breast cancer cells and inhibit oncogenic NOTCH signaling through epigenetic regulation of MAML2 transcriptional activity.
Stilbenoids remodel the DNA methylation patterns in breast cancer cells and inhibit oncogenic NOTCH signaling through epigenetic regulation of MAML2 transcriptional activity.
复制标题
Stilbenoids重塑乳腺癌细胞中的DNA甲基化模式，并通过MAML2转录活性的表观遗传调节来抑制致癌缺口信号传导。
DOI：
10.1093/carcin/bgw048
复制
发表时间：
2016-07
期刊：
影响因子：
4.7
通讯作者：
Stefanska B
中科院分区：
文献类型：
--
作者：
Lubecka K;Kurzava L;Flower K;Buvala H;Zhang H;Teegarden D;Camarillo I;Suderman M;Kuang S;Andrisani O;Flanagan JM;Stefanska B
我们确定了表观遗传学在乳腺癌NOTCH信号调控中的作用。这可能构成致癌信号激活的共同机制。我们的研究为抗癌方法中的表观遗传靶向策略提供了支持。DNA低甲基化先前与癌症的进展和转移有关。本研究的目的是研究被认为具有抗癌作用的芪类化合物、白藜芦醇和紫檀芪是否会靶向具有致癌功能的基因进行从头甲基化和沉默，从而导致相关信号通路失活。在Illumina 450K之后，全基因组DNA甲基化分析显示，stilbenoids改变了乳腺癌细胞的DNA甲基化模式。平均75%的差异甲基化基因甲基化增加，这些基因富集致癌功能，包括NOTCH信号通路。MAML2是NOTCH靶点的协同激活因子，在增强子区域甲基化，并在对苯乙烯类化合物的反应中转录沉默，这可能解释了NOTCH靶基因的下调。MAML2增强子DNA甲基化的增加与抑制性组蛋白标记的占用增加和激活标记的减少相一致。这种浓缩的染色质结构与DNMT3B的结合和OCT1转录因子在MAML2增强子上的占用减少有关，表明DNMT3B在二苯乙烯类药物治疗后增加MAML2甲基化的作用。我们的研究结果为癌症中致癌信号的表观遗传调控提供了新的见解，并为表观遗传靶向策略作为一种有效的抗癌方法提供了支持。
We established the role for epigenetics in regulation of NOTCH signaling in breast cancer. This may constitute a common mechanism of activation of oncogenic signals. Our study provides support for epigenetic-targeting strategies in anticancer approaches. DNA hypomethylation was previously implicated in cancer progression and metastasis. The purpose of this study was to examine whether stilbenoids, resveratrol and pterostilbene thought to exert anticancer effects, target genes with oncogenic function for de novo methylation and silencing, leading to inactivation of related signaling pathways. Following Illumina 450K, genome-wide DNA methylation analysis reveals that stilbenoids alter DNA methylation patterns in breast cancer cells. On average, 75% of differentially methylated genes have increased methylation, and these genes are enriched for oncogenic functions, including NOTCH signaling pathway. MAML2, a coactivator of NOTCH targets, is methylated at the enhancer region and transcriptionally silenced in response to stilbenoids, possibly explaining the downregulation of NOTCH target genes. The increased DNA methylation at MAML2 enhancer coincides with increased occupancy of repressive histone marks and decrease in activating marks. This condensed chromatin structure is associated with binding of DNMT3B and decreased occupancy of OCT1 transcription factor at MAML2 enhancer, suggesting a role of DNMT3B in increasing methylation of MAML2 after stilbenoid treatment. Our results deliver a novel insight into epigenetic regulation of oncogenic signals in cancer and provide support for epigenetic-targeting strategies as an effective anticancer approach.