Abstract
The Hippo pathway is an oncosuppressor signalling cascade that plays a major role in the control of cell growth, tissue homoeostasis and organ size. Dysregulation of the Hippo pathway leads to aberrant activation of the transcription co-activator YAP (Yes-associated protein) that contributes to tumorigenesis in several tissues. Here we identify glucocorticoids (GCs) as hormonal activators of YAP. Stimulation of glucocorticoid receptor (GR) leads to increase of YAP protein levels, nuclear accumulation and transcriptional activity in vitro and in vivo. Mechanistically, we find that GCs increase expression and deposition of fibronectin leading to the focal adhesion-Src pathway stimulation, cytoskeleton-dependent YAP activation and expansion of chemoresistant cancer stem cells. GR activation correlates with YAP activity in human breast cancer and predicts bad prognosis in the basal-like subtype. Our results unveil a novel mechanism of YAP activation in cancer and open the possibility to target GR to prevent cancer stem cells self-renewal and chemoresistance.
Highlights
The Hippo pathway is an oncosuppressor signalling cascade that plays a major role in the control of cell growth, tissue homoeostasis and organ size
To identify novel signalling pathways able to control YAP activation in breast cancer we performed a high-content, fluorescence microscopy-based, high-throughput screening using a library of FDA: Food and Drug Administration (FDA)-approved drugs composed of a collection of 640 clinically used compounds with known and well-characterized bioactivity, safety and bioavailability[11]
We analysed the glucocorticoid receptor (GR) chromatin immunoprecipitation (ChIP)-Seq data set of Dex-stimulated A549 cells derived from the ENCODE project and we identified and validated a stringent ChIP-Seq peak in the fibronectin 1 (FN1) promoter, supporting that FN1 is a direct target of GR that could activate YAP by reinforcing cell adhesion to extracellular matrix (ECM) (Supplementary Fig. 3a,b)
Summary
The Hippo pathway is an oncosuppressor signalling cascade that plays a major role in the control of cell growth, tissue homoeostasis and organ size. Dysregulation of the Hippo pathway leads to aberrant activation of the transcription co-activator YAP (Yes-associated protein) that contributes to tumorigenesis in several tissues. Stimulation of glucocorticoid receptor (GR) leads to increase of YAP protein levels, nuclear accumulation and transcriptional activity in vitro and in vivo. We find that GCs increase expression and deposition of fibronectin leading to the focal adhesion-Src pathway stimulation, cytoskeleton-dependent YAP activation and expansion of chemoresistant cancer stem cells. We identify glucocorticoids (GCs) as hormonal activators of YAP in breast cancer cells. We find that in breast cancer cells the activation of glucocorticoid receptor (GR) is fundamental for CSCs selfrenewal and chemoresistance and that this effect is the consequence of the transcriptional activity of activated YAP. Our results unveil an unpredicted layer of YAP regulation and put the GR–YAP axis at the cornerstone of a potential new therapeutic strategy to target CSCs in breast cancer
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