Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3rd Street, San Francisco, CA 94158, USA.
Cell Rep. 2019 Apr 2;27(1):294-306.e5. doi: 10.1016/j.celrep.2019.02.111.
The PI3K pathway integrates extracellular stimuli to phosphorylate effectors such as AKT and serum-and-glucocorticoid-regulated kinase (SGK1). We have previously reported that the PI3K pathway regulates estrogen receptor (ER)-dependent transcription in breast cancer through the phosphorylation of the lysine methyltransferase KMT2D by AKT. Here, we show that PI3Kα inhibition, via a negative-feedback loop, activates SGK1 to promote chromatin-based regulation of ER-dependent transcription. PI3K/AKT inhibitors activate ER, which promotes SGK1 transcription through direct binding to its promoter. Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity. Thus, SGK1 regulates the chromatin landscape and ER-dependent transcription via the direct phosphorylation of KMT2D. These findings reveal an ER-SGK1-KMT2D signaling circuit aimed to attenuate ER response through a role for SGK1 to program chromatin and ER transcriptional output.
PI3K 通路整合细胞外刺激，使效应物如 AKT 和血清和糖皮质激素调节激酶（SGK1）磷酸化。我们之前曾报道过，PI3K 通路通过 AKT 对赖氨酸甲基转移酶 KMT2D 的磷酸化，调节乳腺癌中雌激素受体（ER）依赖性转录。在这里，我们表明，通过负反馈回路，PI3Kα 抑制会激活 SGK1，以促进基于染色质的 ER 依赖性转录调控。PI3K/AKT 抑制剂激活 ER，通过直接结合其启动子促进 SGK1 的转录。升高的 SGK1 反过来磷酸化 KMT2D，抑制其功能，导致组蛋白 H3（H3K4）上赖氨酸 4 的甲基化丧失和 ER 基因座的抑制性染色质状态，从而减弱 ER 活性。因此，SGK1 通过直接磷酸化 KMT2D 来调节染色质景观和 ER 依赖性转录。这些发现揭示了一个 ER-SGK1-KMT2D 信号通路，旨在通过 SGK1 的作用来调节染色质和 ER 转录输出，从而减弱 ER 反应。
