University of British Columbia, 2329 West Mall, Vancouver, BC, V6T 1Z4, Canada.
Department of Biomedical Chemistry, Medical University of Lodz, al. Tadeusza Kościuszki 4, 90-419, Łódź, Poland.
Mol Nutr Food Res. 2019 Oct;63(19):e1801386. doi: 10.1002/mnfr.201801386. Epub 2019 Jul 31.
Loci-specific increase in DNA methylation occurs in cancer and may underlie gene silencing. It is investigated whether dietary stilbenoids, resveratrol, and pterostilbene exert time-dependent effects on DNA methylation patterns and specifically methylation-silenced tumor suppressor genes in breast cancer cells.
Following genome-wide DNA methylation analysis with Illumina-450K, changes characteristic of early and late response to stilbenoids are identified. Interestingly, often the same genes but at different CpG loci, the same gene families, or the same functional gene categories are affected. CpG loci that lose methylation in exposed cells correspond to genes functionally associated with cancer suppression. There is a group of genes, including SEMA3A, at which the magnitude of hypomethylation in response to stilbenoids rises with increasing invasive potential of cancer cells. Decreased DNA methylation at SEMA3A promoter and concomitant gene upregulation coincide with increased occupancy of active histone marks. Open chromatin upon exposure to stilbenoids may be linked to decreased DNMT3A binding followed by increased NF1C transcription factor occupancy. Sequestration of DNMT3A is possibly a result of stilbenoid-mediated increase in SALL3 expression, which was previously shown to bind and inhibit DNMT3A activity.
The findings define mechanistic players in stilbenoid-mediated epigenetic reactivation of genes suppressing cancer.
癌症中会出现特定基因座的 DNA 甲基化增加，这可能是基因沉默的基础。本研究探讨了膳食白藜芦醇和 pterostilbene 是否会对乳腺癌细胞中的 DNA 甲基化模式和特定的甲基化沉默肿瘤抑制基因产生时间依赖性影响。
采用 Illumina-450K 进行全基因组 DNA 甲基化分析后，确定了对白藜芦醇早期和晚期反应的特征变化。有趣的是，通常相同的基因但在不同的 CpG 基因座、相同的基因家族或相同的功能基因类别受到影响。在暴露细胞中失去甲基化的 CpG 基因座与功能上与癌症抑制相关的基因相对应。存在一组基因，包括 SEMA3A，其对白藜芦醇反应的低甲基化程度随着癌细胞侵袭潜能的增加而增加。SEMA3A 启动子处的 DNA 甲基化降低以及伴随的基因上调与活性组蛋白标记的占有率增加相吻合。暴露于白藜芦醇后开放的染色质可能与 DNMT3A 结合减少有关，随后 NF1C 转录因子占有率增加。DNMT3A 的隔离可能是白藜芦醇介导的 SALL3 表达增加的结果，先前的研究表明 SALL3 可以结合并抑制 DNMT3A 的活性。
这些发现定义了白藜芦醇介导的基因表观遗传再激活中涉及的机制性参与者，这些基因可抑制癌症。
