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Post-translational inhibition of YAP oncogene expression by 4-hydroxynonenal in bladder cancer cells
Marie Angele Cucci1, Alessandra Compagnone2, Martina Daga1
1Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Regione Gonzole 10, 10043, Orbassano, Turin, Italy.
Abstract:
The transcriptional regulator YAP plays an important role in cancer progression and is negatively controlled by the Hippo pathway. YAP is frequently overexpressed in human cancers, including bladder cancer. Interestingly, YAP expression and activity can be inhibited by pro-oxidant conditions; moreover, YAP itself can also affect the cellular redox status through multiple mechanisms. 4-Hydroxynonenal (HNE), the most intensively studied end product of lipid peroxidation, is a pro-oxidant agent able to deplete GSH and has an anti-tumoral effect by affecting multiple signal pathways, including the down-regulation of oncogene expressions. These observations prompted us to investigate the effect of HNE on YAP expression and activity. We demonstrated that HNE inhibited YAP expression and its target genes in bladder cancer cells through a redox-dependent mechanism. Moreover, the YAP down-regulation was accompanied by an inhibition of proliferation, migration, invasion, and angiogenesis, as well as by an accumulation of cells in the G2/M phase of cell cycle and by an induction of apoptosis. We also established the YAP role in inhibiting cell viability and inducing apoptosis in HNE-treated cells by using an expression vector for YAP. Furthermore, we identified a post-translational mechanism for the HNE-induced YAP expression inhibition, involving an increase of YAP phosphorylation and ubiquitination, leading to proteasomal degradation. Our data established that HNE can post-translationally down-regulate YAP through a redox-dependent mechanism and that this modulation can contribute to determining the specific anti-cancer effects of HNE.
Insights
4-Hydroxynonenal (HNE) inhibits the YAP oncogene in bladder cancer cells via a redox-dependent mechanism. This YAP down-regulation reduces cancer progression and induces apoptosis, revealing a novel anti-cancer effect of HNE.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The transcriptional regulator YAP is crucial in cancer progression and is often overexpressed in human cancers, including bladder cancer.
- YAP activity is negatively regulated by the Hippo pathway and can be inhibited by pro-oxidant conditions.
- 4-Hydroxynonenal (HNE), a lipid peroxidation product, exhibits anti-tumoral effects by influencing signaling pathways and down-regulating oncogenes.
Purpose of the Study:
- To investigate the effect of HNE on YAP expression and activity in bladder cancer cells.
- To elucidate the underlying redox-dependent mechanisms of HNE's action on YAP.
- To determine the contribution of YAP modulation to HNE's anti-cancer effects.
Main Methods:
- Treatment of bladder cancer cells with HNE.
- Analysis of YAP expression and target gene activity.
- Assessment of cell proliferation, migration, invasion, angiogenesis, cell cycle, and apoptosis.
- Investigation of YAP's role using an expression vector.
- Identification of post-translational modifications of YAP (phosphorylation, ubiquitination).
Main Results:
- HNE inhibited YAP expression and its target genes in bladder cancer cells through a redox-dependent mechanism.
- YAP down-regulation by HNE led to reduced proliferation, migration, invasion, and angiogenesis.
- HNE treatment caused G2/M cell cycle arrest and induced apoptosis.
- HNE increased YAP phosphorylation and ubiquitination, leading to proteasomal degradation.
- Restoring YAP expression counteracted HNE's effects on cell viability and apoptosis.
Conclusions:
- HNE post-translationally down-regulates YAP in bladder cancer cells via a redox-dependent mechanism.
- This HNE-mediated YAP inhibition contributes to its anti-cancer properties, including reduced proliferation and induced apoptosis.
- Targeting YAP with agents like HNE represents a potential therapeutic strategy for bladder cancer.
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