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Published on: October 10, 2017
Curcumin promotes KLF5 proteasome degradation through downregulating YAP/TAZ in bladder cancer cells
1Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. gaoyangxjtu@126.com.
Abstract:
KLF5 (Krüppel-like factor 5) plays critical roles in normal and cancer cell proliferation through modulating cell cycle progression. In this study, we demonstrated that curcumin targeted KLF5 by promoting its proteasome degradation, but not by inhibiting its transcription in bladder cancer cells. We also demonstrated that lentivirus-based knockdown of KLF5 inhibited cancer cell growth, while over-expression of a Flag-tagged KLF5 could partially reverse the effects of curcumin on cell growth and cyclin D1 expression. Furthermore, we found that curcumin could down-regulate the expression of Hippo pathway effectors, YAP and TAZ, which have been reported to protect KLF5 protein from degradation. Indeed, knockdown of YAP by small interfering RNA caused the attenuation of KLF5 protein, but not KLF5 mRNA, which was reversed by co-incubation with proteasome inhibitor. A xenograft assay in nude mice finally proved the potent inhibitory effects of curcumin on tumor growth and the pro-proliferative YAP/TAZ/KLF5/cyclin D1 axis. Thus, our data indicates that curcumin promotes KLF5 proteasome-dependent degradation through targeting YAP/TAZ in bladder cancer cells and also suggests the therapeutic potential of curcumin in the treatment of bladder cancer.
Insights
Curcumin targets Krüppel-like factor 5 (KLF5) for proteasome degradation in bladder cancer cells. This action inhibits cancer cell proliferation by down-regulating the YAP/TAZ pathway, suggesting therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Krüppel-like factor 5 (KLF5) is crucial for cell proliferation in normal and cancerous tissues.
- Dysregulation of KLF5 is implicated in various cancers, including bladder cancer.
- The Hippo pathway, involving YAP and TAZ, influences cell growth and survival.
Purpose of the Study:
- To investigate the mechanism by which curcumin affects KLF5 expression in bladder cancer cells.
- To elucidate the role of the YAP/TAZ pathway in curcumin's anti-cancer effects.
- To evaluate the therapeutic potential of curcumin in bladder cancer models.
Main Methods:
- Cell culture of bladder cancer lines.
- Lentivirus-mediated gene knockdown and overexpression.
- Western blotting and quantitative PCR for protein and mRNA analysis.
- Proteasome inhibitor treatment.
- Xenograft mouse models for in vivo efficacy assessment.
Main Results:
- Curcumin promotes proteasome-dependent degradation of KLF5, not transcriptional inhibition.
- Knockdown of KLF5 inhibits bladder cancer cell growth; KLF5 overexpression partially reverses curcumin's effects.
- Curcumin down-regulates YAP and TAZ expression.
- YAP knockdown leads to KLF5 protein attenuation, reversible by proteasome inhibitors.
- Curcumin inhibits tumor growth in vivo and affects the YAP/TAZ/KLF5/cyclin D1 axis.
Conclusions:
- Curcumin induces proteasome-dependent degradation of KLF5 by targeting YAP/TAZ in bladder cancer.
- The YAP/TAZ/KLF5/cyclin D1 pathway is a pro-proliferative axis in bladder cancer targeted by curcumin.
- Curcumin demonstrates significant therapeutic potential for bladder cancer treatment.
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