Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Int J Mol Sci. 2018 Jun 13;19(6):1754. doi: 10.3390/ijms19061754.
Dietary compounds that possess the properties of altering epigenetic processes are gaining popularity as targets for cancer prevention studies. These compounds when administered at optimal concentrations and especially in combination can have enhanced effects in cancer prevention or therapy. It is important to study the interaction of two or more compounds in order to assess their role in enhancing prevention. Genistein (GEN), found in soy, has been extensively studied for its role as an epigenetic modifier especially as a DNA methyltransferase (DNMT) inhibitor and sulforaphane (SFN), found in cruciferous vegetables, is known as a histone deacetylase (HDAC) inhibitor. However, very little is known about the effects of these two compounds in conjunction in breast cancer prevention or therapy. In our current study, we determined that, at certain doses, the compounds have synergistic effects in decreasing cellular viability of breast cancer cell lines. Our results indicate that the combination of GEN and SFN is much more effective than their single doses in increasing the rate of apoptosis and lowering the colony forming potential of these cells. We determined that these compounds inhibit cell cycle progression to G2 phase in MDA-MB-231 and G1 phase in MCF-7 breast cancer cell lines. Additionally, we determined that the combination is effective as an HDAC and histone methyltransferase (HMT) inhibitor. Furthermore, we demonstrated that this combination downregulates the levels of HDAC2 and HDAC3 both at the mRNA and protein levels. We also found that these compounds have the potential to downregulate KLF4 levels, which plays an important role in stem cell formation. The combination of GEN and SFN is also effective in downregulating hTERT levels, which is known to be activated when KLF4 binds to its promoter region. Our hypothesis is further strengthened by studies, where the combination is administered to transgenic mice in the form of genistein and SFN-enriched broccoli sprouts. We have demonstrated that the combination is more effective in preventing or treating mammary cancer via extending tumor latency and reducing tumor volumes/sizes than either of these dietary components administered alone. These results are consistent with our study suggesting potential preventive and therapeutic effects of this novel dietary combinatorial approach against breast cancer.
具有改变表观遗传过程特性的膳食化合物作为癌症预防研究的靶点越来越受到关注。这些化合物在最佳浓度下给药，特别是联合给药时，在癌症预防或治疗中可以具有增强的效果。研究两种或更多化合物的相互作用以评估它们在增强预防中的作用非常重要。大豆中存在的染料木黄酮（GEN）已被广泛研究，作为一种表观遗传修饰物，特别是作为 DNA 甲基转移酶（DNMT）抑制剂，而十字花科蔬菜中存在的萝卜硫素（SFN）则作为组蛋白去乙酰化酶（HDAC）抑制剂而为人所知。然而，关于这两种化合物联合用于预防或治疗乳腺癌的效果知之甚少。在我们目前的研究中，我们确定在某些剂量下，这些化合物在降低乳腺癌细胞系的细胞活力方面具有协同作用。我们的结果表明，GEN 和 SFN 的组合比它们的单一剂量更有效地增加这些细胞的凋亡率并降低集落形成能力。我们确定这些化合物抑制 MDA-MB-231 中的细胞周期进展到 G2 期和 MCF-7 中的 G1 期。此外，我们确定该组合作为 HDAC 和组蛋白甲基转移酶（HMT）抑制剂是有效的。此外，我们证明该组合有效地下调 HDAC2 和 HDAC3 的水平，无论是在 mRNA 还是蛋白质水平。我们还发现，这些化合物具有下调 KLF4 水平的潜力，KLF4 在干细胞形成中起重要作用。GEN 和 SFN 的组合也有效地下调 hTERT 水平，已知当 KLF4 与其启动子区域结合时，hTERT 水平会被激活。我们的假设得到了进一步的研究支持，其中以富含 GEN 和 SFN 的西兰花芽的形式向转基因小鼠给予该组合。我们已经证明，与单独给予这些饮食成分中的任何一种相比，该组合在通过延长肿瘤潜伏期和减少肿瘤体积/大小来预防或治疗乳腺癌方面更有效。这些结果与我们的研究一致，该研究表明这种新型饮食组合方法对乳腺癌具有潜在的预防和治疗作用。
