A Ras-LSD1 axis activates PI3K signaling through PIK3IP1 suppression

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.