Lubecka Katarzyna, Kurzava Lucinda, Flower Kirsty, Buvala Hannah, Zhang Hao, Teegarden Dorothy, Camarillo Ignacio, Suderman Matthew, Kuang Shihuan, Andrisani Ourania, Flanagan James M, Stefanska Barbara
Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.
Epigenetic Unit, Department of Surgery and Cancer, Imperial College London, London, UK.
Carcinogenesis. 2016 Jul;37(7):656-68. doi: 10.1093/carcin/bgw048. Epub 2016 Apr 28.
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.
DNA低甲基化先前被认为与癌症进展和转移有关。本研究的目的是检验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。在进行Illumina 450K全基因组DNA甲基化分析后发现，芪类化合物可改变乳腺癌细胞中的DNA甲基化模式。平均而言，75%的差异甲基化基因的甲基化水平升高，这些基因富含致癌功能，包括NOTCH信号通路。NOTCH靶点的共激活因子MAML2在增强子区域发生甲基化，并在芪类化合物作用下转录沉默，这可能解释了NOTCH靶点基因的下调。MAML2增强子处DNA甲基化的增加与抑制性组蛋白标记的占据增加以及激活标记的减少相一致。这种浓缩的染色质结构与DNMT3B的结合以及MAML2增强子处OCT1转录因子的占据减少有关，表明DNMT3B在芪类化合物处理后增加MAML2甲基化中发挥作用。我们的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。
