A Ras-LSD1 axis activates PI3K signaling through PIK3IP1 suppression

Kyunghee Lee,Pei Ju Liao,David M Virshup,Sang Hyun Lee,Mayumi Kitagawa

doi:10.1038/s41389-019-0185-4

Kyunghee Lee, Pei Ju Liao + Show 3 more

Open Access

https://doi.org/10.1038/s41389-019-0185-4

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Abstract

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.

Highlights

Introduction ThePI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling pathways transmit signals from receptor tyrosine kinases (RTKs) to downstream effector networks regulating cell growth, survival, and proliferation in response to external cues[1,2]
We recently reported that a novel compound, named a131, highly increases the PIK3IP1 expression and this causes the PI3K/Akt/mTOR pathway inhibitions in normal BJ-HRasV12-ER cells but not in transformed counterparts
Conditional overexpression of PIK3IP1 suppresses Rasinduced transformation We previously found that PIK3IP1 mRNA expression level was significantly downregulated in most Ras/Rafmutant cancer cells[8]

Summary

Introduction

PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling pathways transmit signals from receptor tyrosine kinases (RTKs) to downstream effector networks regulating cell growth, survival, and proliferation in response to external cues[1,2]. We recently reported that a novel compound, named a131, highly increases the PIK3IP1 expression and this causes the PI3K/Akt/mTOR pathway inhibitions in normal BJ-HRasV12-ER cells but not in transformed counterparts. 4-HT-induced H-RasV12-ER activation is sufficient to reactivate the PI3K/Akt/mTOR pathway through downregulating mRNA and protein levels of PIK3IP1 in a131-treated normal BJ-H-RasV12-ER cells. Using Ras-activated cancer cells and clinical samples from patients with colorectal and lung adenocarcinomas, we have described the underlying mechanism for cross-activation, positive cross-talk, Lee et al Oncogenesis (2020)9:2 and reactivation of PI3K signaling in cancer and further supports efforts to pharmacologically target LSD1

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