Triple-negative breast cancers (TNBC) that produce nitric oxide (NO) are more aggressive, and the expression of the inducible form of nitric oxide synthase (NOS2) is a negative prognostic indicator. In these studies, we set out to investigate potential therapeutic strategies to counter the tumor-permissive properties of NO. We found that exposure to NO increased proliferation of TNBC cells and that treatment with the histone deacetylase inhibitor Vorinostat (SAHA) prevented this proliferation. When histone acetylation was measured in response to NO and/or SAHA, NO significantly decreased acetylation on histone 3 lysine 9 (H3K9ac) and SAHA increased H3K9ac. If NO and SAHA were sequentially administered to cells (in either order), an increase in acetylation was observed in all cases. Mechanistic studies suggest that the “deacetylase” activity of NO does not involve S -nitrosothiols or soluble guanylyl cyclase activation. The observed decrease in histone acetylation by NO required the interaction of NO with cellular iron pools and may be an overriding effect of NO-mediated increases in histone methylation at the same lysine residues. Our data revealed a novel pathway interaction of Vorinostat and provides new insight in therapeutic strategy for aggressive TNBCs.

中文翻译：

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伏立诺他通过阻止一氧化氮驱动的组蛋白脱乙酰化在三阴性乳腺癌细胞中表现出抗癌作用


产生一氧化氮 (NO) 的三阴性乳腺癌 (TNBC) 更具侵袭性，诱导型一氧化氮合酶 (NOS2) 的表达是一个阴性预后指标。在这些研究中，我们着手研究潜在的治疗策略来对抗 NO 的肿瘤允许特性。我们发现，暴露于 NO 会增加 TNBC 细胞的增殖，而组蛋白脱乙酰酶抑制剂伏立诺他 (SAHA) 治疗可阻止这种增殖。当测量组蛋白乙酰化对 NO 和/或 SAHA 的反应时，NO 显着降低了组蛋白 3 赖氨酸 9 (H3K9ac) 上的乙酰化，而 SAHA 则增加了 H3K9ac。如果将 NO 和 SAHA 按顺序给予细胞（以任一顺序），则在所有情况下都会观察到乙酰化的增加。机理研究表明，NO 的“脱乙酰酶”活性不涉及 S-亚硝基硫醇或可溶性鸟苷酸环化酶的激活。观察到的 NO 引起的组蛋白乙酰化减少需要 NO 与细胞铁库的相互作用，并且可能是 NO 介导的相同赖氨酸残基处组蛋白甲基化增加的压倒性作用。我们的数据揭示了伏立诺他的一种新的通路相互作用，并为侵袭性 TNBC 的治疗策略提供了新的见解。