PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression.,Cell Reports

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PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression.
Cell Reports ( IF 7.5 ) Pub Date : 2019-04-02 , DOI: 10.1016/j.celrep.2019.02.111
Eneda Toska ₁ , Pau Castel ₂ , Sagar Chhangawala ₃ , Amaia Arruabarrena-Aristorena ₁ , Carmen Chan ₁ , Vasilis C Hristidis ₁ , Emiliano Cocco ₁ , Mirna Sallaku ₁ , Guotai Xu ₁ , Jane Park ₄ , Gerard Minuesa ₅ , Sophie G Shifman ₁ , Nicholas D Socci ₆ , Richard Koche ₄ , Christina S Leslie ₃ , Maurizio Scaltriti ₇ , José Baselga ₈

Affiliation

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.
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Center of Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Molecular Pharmacology Program, Memorial Sloan Kettering Institute, New York, NY 10065, USA.
Bioinformatics Core, Memorial Sloan Kettering Cancer Center, 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; Department of Pathology, Memorial Sloan Kettering Cancer Center, 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; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Research & Development Oncology, AstraZeneca Pharmaceuticals, Gaithersburg, MD 20878, USA.

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.

中文翻译：

PI3K抑制通过反馈回路激活SGK1，以促进基于染色质的ER依赖性基因表达调控。

PI3K途径将细胞外刺激整合到磷酸化效应子（如AKT和血清和糖皮质激素调节的激酶（SGK1））上。我们以前曾报道过PI3K途径通过AKT磷酸化赖氨酸甲基转移酶KMT2D来调节乳腺癌中雌激素受体（ER）依赖性转录。在这里，我们显示PI3Kα抑制通过负反馈回路激活SGK1以促进基于染色质的ER依赖性转录调节。PI3K / AKT抑制剂激活ER，ER通过直接与其启动子结合而促进SGK1转录。升高的SGK1反过来会磷酸化KMT2D，抑制其功能，导致组蛋白H3（H3K4）上赖氨酸4的甲基化丧失，并在ER位点处抑制染色质，从而减弱ER活性。因此，SGK1通过KMT2D的直接磷酸化调节染色质景观和ER依赖性转录。这些发现揭示了一个ER-SGK1-KMT2D信号转导电路，旨在通过SGK1编程染色质和ER转录输出的作用来减弱ER反应。

更新日期：2019-04-03

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