Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC. MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC.

中文翻译：

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高胰岛素血症促进三阴性乳腺癌中异常的组蛋白乙酰化。


高胰岛素血症是指血液中胰岛素相对于葡萄糖过量，被认为是三阴性乳腺癌 (TNBC) 患者的不良预后指标。 mTOR 是胰岛素的下游效应子，可增强线粒体的生物发生和活性，从而增加乙酰辅酶A 前体。反过来，增加的乙酰辅酶A可以被核乙酰转移酶用于组蛋白乙酰化，这是基因组调控的一个关键特征。虽然胰岛素下游的信号通路已经建立了一段时间，但胰岛素对染色质的影响仍不清楚。我们假设高胰岛素血症诱导的代谢变化导致 TNBC 中组蛋白乙酰化的全基因组变化。 MDA-MB-231 细胞被异种移植到高胰岛素血症和野生型小鼠中。与正常胰岛素条件下的肿瘤相比，高胰岛素血症小鼠的肿瘤表现出组蛋白乙酰化水平升高。我们表明，体外胰岛素治疗通过 PI3K/AKT/mTOR 途径导致染色质相关组蛋白乙酰化的整体增加，特别是在 H3K9 处。全基因组分析表明，大多数启动子区域在胰岛素治疗后组蛋白乙酰化增加。此外，胰岛素还会诱导细胞内活性氧和 DNA 损伤灶水平升高。这些结果证明了高胰岛素血症对通过染色质改变的基因调控的影响，以及针对高胰岛素血症诱导的导致 TNBC 染色质功能障碍的过程的重要性。