PI3K inhibition activates SGK1 via a feedback loop to promote chromatin-based regulation of ER-dependent gene expression

The phosphoinositide 3-kinase (PI3K) pathway integrates extracellular stimuli to phosphorylate and activate key downstream effectors such as AKT and serum-and glucocorticoid-inducible kinase (SGK1). We have previously reported that the PI3K pathway regulates ER-dependent transcription in breast cancer through the phosphorylation of the epigenetic regulator KMT2D by AKT. Here, we provide new insights into how the PI3K pathway propagates its effects to control KMT2D and ER function via SGK1, another PI3K downstream effector. Specifically, we show that PI3K inhibition, via a negative feedback loop, activates SGK1 to promote chromatin-based regulation of ER-dependent gene expression. PI3K/AKT inhibitors activate ER, which subsequently promotes SGK1 transcription through direct binding to its promoter. Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function and altering the chromatin landscape to attenuate ER-dependent expression. Thus, we have determined that 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 previously unknown role for SGK1 to program chromatin and ER transcriptional output. Genome-wide analysis of chromatin accessibility upon overexpression of catalytically active SGK1 S422D

磷脂酰肌醇3-激酶（phosphoinositide 3-kinase, PI3K）通路可整合胞外刺激信号，通过磷酸化激活AKT、血清与糖皮质激素诱导激酶（serum-and glucocorticoid-inducible kinase, SGK1）等关键下游效应因子。本团队此前曾报道，PI3K通路可通过AKT磷酸化表观遗传调控因子KMT2D，调控乳腺癌中雌激素受体（Estrogen Receptor, ER）依赖的转录过程。本研究进一步揭示了PI3K通路如何通过另一下游效应因子SGK1传递信号，以调控KMT2D与ER的功能。具体而言，PI3K抑制可通过负反馈环路激活SGK1，进而促进ER依赖基因表达的染色质层面调控。PI3K/AKT抑制剂可激活ER，后者通过直接结合SGK1的启动子区域，促进SGK1的转录。升高的SGK1则可进一步磷酸化KMT2D，抑制其功能并改变染色质景观，最终减弱ER依赖的基因表达。综上，本研究证实SGK1可通过直接磷酸化KMT2D，调控染色质景观与ER依赖的转录过程。上述发现揭示了一条ER-SGK1-KMT2D信号环路，该环路可通过SGK1此前未被报道的染色质编程与ER转录输出调控功能，减弱ER应答反应。本研究对过表达催化活性型SGK1（S422D）后的染色质可及性开展了全基因组分析。