PI3K Interacting Protein 1 (PIK3IP1) is a suppressor of the PI3K/Akt/mTOR pathway. We previously reported that activated Ras suppresses PIK3IP1 expression to positively regulate the PI3K pathway in cancer cells. Using doxycycline-inducible PIK3IP1, here we confirm that reversing the effect of Ras by inducing expression of PIK3IP1 suppresses Ras-induced anchorage-independent growth, supporting the central role of PIK3IP1 in transformation. However, the molecular mechanisms by which Ras-activation that causes loss of PIK3IP1 expression are unknown. We find that Ras activity represses PIK3IP1 expression via the recruitment of lysine-specific demethylase 1 (LSD1) to the PIK3IP1 gene promoter and enhancer, resulting in erasure of active histone marks. These studies demonstrate cross-activation of Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways, where Ras decommissions PIK3IP1 gene expression by enhancing LSD1 and its corepressor activities to suppress PIK3IP1 transcription.

中文翻译：

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Ras-LSD1轴通过抑制PIK3IP1激活PI3K信号。

PI3K相互作用蛋白1（PIK3IP1）是PI3K / Akt / mTOR途径的抑制剂。我们先前曾报道过，活化的Ras抑制PIK3IP1的表达，从而积极调节癌细胞中的PI3K途径。使用强力霉素诱导的PIK3IP1，在这里我们证实通过诱导PIK3IP1的表达来逆转Ras的作用可抑制Ras诱导的锚定非依赖性生长，从而支持PIK3IP1在转化中的核心作用。然而，引起PIK3IP1表达丧失的Ras激活的分子机制尚不清楚。我们发现，Ras活性通过赖氨酸特异性脱甲基酶1（LSD1）募集到PIK3IP1基因启动子和增强子来抑制PIK3IP1表达，从而导致活性组蛋白标记的清除。这些研究证明了Ras / Raf / MEK / ERK和PI3K / AKT / mTOR通路的交叉激活，