AKT Inhibition Modulates H3K4 Demethylase Levels in PTEN-Null Prostate Cancer.
AKT Inhibition Modulates H3K4 Demethylase Levels in PTEN-Null Prostate Cancer.
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DOI：
10.1158/1535-7163.mct-18-0141
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发表时间：
2019-03
影响因子：
5.7
通讯作者：
Mukhtar H
中科院分区：
文献类型：
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作者：
Khan MI;Hamid A;Rath S;Ateeq B;Khan Q;Siddiqui IA;Adhami VM;Choudhry H;Zamzami MA;Mukhtar H
AKT 激酶由于其负调节因子 PTEN 缺失而过度激活，会影响癌症生物学的许多方面，包括染色质。 AKT 主要调节乙酰辅酶 A 的产生并使许多组蛋白调节酶磷酸化，从而导致其激活或抑制。因此，了解 AKT 抑制对染色质相关事件的治疗影响至关重要。在这里，我们报告前列腺特异性 PTEN 敲除小鼠中的 AKT 抑制显着诱导 H3K4 的二甲基化和三甲基化，同时 H3K9 乙酰化减少。从机制上讲，我们观察到 AKT 抑制会降低 H3K4 甲基化特异性组蛋白去甲基化酶 KDM5 家族的表达，尤其是转录水平上的 KDM5B 表达。此外，我们观察到 AKT 负向调节 miR-137 水平，从而转录抑制 KDM5B 表达。 miR-137 的过表达显着降低了 KDM5B 并增加了 H3K4 甲基化水平，但未能改变 AKT 磷酸化。总体而言，我们观察到 AKT 主要通过抑制 miR-137 对 KDM5B 进行转录调节。我们的数据确定了 AKT 激酶通过调节 H3K4 甲基化来调节前列腺癌表观基因组的机制。关于 AKT 抑制介导的 H3K4 甲基化诱导的其他研究将有助于设计增强 PI3K/AKT 抑制剂治疗功效的策略。
Hyperactivated AKT kinase due to loss of its negative regulator PTEN influences many aspects of cancer biology including chromatin. AKT primarily regulates acetyl-CoA production and phosphorylates many histone modulating enzymes resulting in their activation or inhibition. Therefore, understanding the therapeutic impact of AKT inhibition on chromatin related events is essential. Here, we report that AKT inhibition in prostate specific PTEN knockout mice significantly induces di- and tri-methylation of H3K4 with concomitant reduction in H3K9 acetylation. Mechanistically, we observed that AKT inhibition reduces expression of the H3K4 methylation specific histone demethylases KDM5 family, especially KDM5B expression at transcriptional levels. Further, we observed that AKT negatively regulates miR-137 levels, which transcriptionally represses KDM5B expression. Overexpression of miR-137 significantly reduced KDM5B and increased H3K4 methylation levels but failed to change AKT phosphorylation. Overall, we observed that AKT transcriptionally regulates KDM5B mainly via repression of miR-137. Our data identify a mechanism by which AKT kinase modulates the prostate cancer epigenome through regulating H3K4 methylation. Additional studies on AKT inhibition mediated induction of H3K4 methylation will help in designing strategies to enhance the therapeutic efficacy of PI3K/AKT inhibitors.