School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551 Singapore.
Institute of Medical Biology, A*STAR, 8A Biomedical Grove, #05-05 Immunos, 138648 Singapore.
Sci Rep. 2017 Jan 12;7:40569. doi: 10.1038/srep40569.
Dietary intake of bioactive phytochemicals including the cruciferous vegetable derivative phenethyl isothiocyanate (PEITC) can reduce risk of human cancers, but possible epigenetic mechanisms of these effects are yet unknown. We therefore sought to identify the molecular basis of PEITC-mediated epigenetic tumor restriction. Colon cancer cells treated with low-dose PEITC for >1 month exhibited stable alterations in expression profile of epigenetic writers/erasers and chromatin-binding of histone deacetylases (HDACs) and Polycomb-group (PcG) proteins. Sustained PEITC exposure not only blocked HDAC binding to euchromatin but was also associated with hypomethylation of PcG target genes that are typically hypermethylated in cancer. Furthermore, PEITC treatment induced expression of pro-apoptotic genes in tumor cells, which was partially reversed by overexpression of PcG member BMI-1, suggesting opposing roles for PEITC and PcG proteins in control of tumor progression. These data demonstrate that PEITC regulates chromatin binding of key epigenetic writers/erasers and PcG complexes to restrict tumor development.
包括十字花科蔬菜衍生的苯乙基异硫氰酸酯（PEITC）在内的生物活性植物化学物质的饮食摄入可以降低人类癌症的风险，但这些影响的可能表观遗传机制尚不清楚。因此，我们试图确定 PEITC 介导的表观遗传肿瘤抑制的分子基础。用低剂量 PEITC 处理超过 1 个月的结肠癌细胞表现出表观遗传写入器/擦除器表达谱和组蛋白去乙酰化酶（HDACs）和 Polycomb-group（PcG）蛋白与染色质结合的稳定改变。持续暴露于 PEITC 不仅阻止了 HDAC 与常染色质的结合，而且还与 PcG 靶基因的低甲基化有关，这些基因在癌症中通常呈高甲基化。此外，PEITC 处理诱导肿瘤细胞中促凋亡基因的表达，而过表达 PcG 成员 BMI-1 部分逆转了这种表达，这表明 PEITC 和 PcG 蛋白在控制肿瘤进展方面的作用相反。这些数据表明，PEITC 调节关键表观遗传写入器/擦除器和 PcG 复合物与染色质的结合，以限制肿瘤的发展。
