Selenium nanoparticles modulate histone methylation via lysine methyltransferase activity and S-adenosylhomocysteine depletion.
Selenium nanoparticles modulate histone methylation via lysine methyltransferase activity and S-adenosylhomocysteine depletion.
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DOI：
10.1016/j.redox.2023.102641
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发表时间：
2023-05
期刊：
影响因子：
11.4
通讯作者：
Conlan RS
中科院分区：
文献类型：
--
作者：
Toubhans B;Alkafri N;Quintela M;James DW;Bissardon C;Gazze S;Knodel F;Proux O;Gourlan AT;Rathert P;Bohic S;Gonzalez D;Francis LW;Charlet L;Conlan RS
在生理水平上，微量元素硒通过在抗氧化酶中掺入硒半胱氨酸在氧化还原反应中起关键作用。硒也被评估为一种潜在的抗癌剂，其中硒纳米颗粒已被证明是有效的，并且在体内耐受良好，剂量与可溶性硒一样有毒。用血清白蛋白或天然碱性多糖壳聚糖包裹这种纳米粒子，也有助于提高生物相容性和生物利用度。在此，我们展示了硒在用血清白蛋白或壳聚糖包被无机硒纳米颗粒处理的卵巢癌细胞模型中调节组蛋白甲基化的新作用。在诱导硫氧还蛋白还原酶表达、ROS活性和癌细胞毒性的同时，包被纳米颗粒引起组蛋白甲基化显著增加。具体来说，硒纳米颗粒引发了组蛋白3赖氨酸K9和K27位点甲基化的增加，组蛋白标记参与基因表达的激活和抑制，从而表明硒在这些表观遗传过程中发挥了基本作用。使用组蛋白赖氨酸甲基转移酶EZH2 （H3K27）和G9a/EHMT2 （H3K9）的化学抑制剂证实了这种直接作用，两者都阻断了硒对组蛋白甲基化的影响。硒的这种新作用支持了组蛋白甲基化的独特功能，这是由于s -腺苷型同型半胱氨酸的减少而发生的，s -腺苷型半胱氨酸是赖氨酸甲基转移酶的内源性抑制剂，是s -腺苷型蛋氨酸在一碳代谢途径中甲基转移的代谢产物。这些观察结果为硒纳米颗粒的作用提供了重要的新见解。现在重要的是考虑经典的抗氧化作用和新的组蛋白甲基化作用，这一关键的氧化还原元素在癌症治疗和其他应用中的发展。
At physiological levels, the trace element selenium plays a key role in redox reactions through the incorporation of selenocysteine in antioxidant enzymes. Selenium has also been evaluated as a potential anti-cancer agent, where selenium nanoparticles have proven effective, and are well tolerated in vivo at doses that are toxic as soluble Se. The use of such nanoparticles, coated with either serum albumin or the naturally occurring alkaline polysaccharide chitosan, also serves to enhance biocompatibility and bioavailability. Here we demonstrate a novel role for selenium in regulating histone methylation in ovarian cancer cell models treated with inorganic selenium nanoparticles coated with serum albumin or chitosan. As well as inducing thioredoxin reductase expression, ROS activity and cancer cell cytotoxicity, coated nanoparticles caused significant increases in histone methylation. Specifically, selenium nanoparticles triggered an increase in the methylation of histone 3 at lysines K9 and K27, histone marks involved in both the activation and repression of gene expression, thus suggesting a fundamental role for selenium in these epigenetic processes. This direct function was confirmed using chemical inhibitors of the histone lysine methyltransferases EZH2 (H3K27) and G9a/EHMT2 (H3K9), both of which blocked the effect of selenium on histone methylation. This novel role for selenium supports a distinct function in histone methylation that occurs due to a decrease in S-adenosylhomocysteine, an endogenous inhibitor of lysine methyltransferases, the metabolic product of methyl-group transfer from S-adenosylmethionine in the one-carbon metabolism pathway. These observations provide important new insights into the action of selenium nanoparticles. It is now important to consider both the classic antioxidant and novel histone methylation effects of this key redox element in its development in cancer therapy and other applications.
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影响因子：
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作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
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影响因子：
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作者：
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