Journal Article

Silibinin relieves UVB-induced apoptosis of human skin cells by inhibiting the YAP-p73 pathway

Otkur, Wuxiyar, Mizuno, Kazunori, Liu, Wei-wei, Hayashi, Toshihiko, Hattori, Shunji, Zhu, Yu-ying, Song, Xiao-yu, Fujisaki, Hitomi, Wang, Fang, Ikejima, Takashi, Li, Can

2022

Overview

Excessive exposure to UVB induces skin diseases. Silibinin, a flavonolignan used for treating liver diseases, is found to be effective against UVB-caused skin epidermal and dermal cell damage. In this study we investigated the molecular mechanisms underlying. Human nonmalignant immortalized keratinocyte HaCaT cells and neonatal human foreskin fibroblasts HFFs were exposed to UVB irradiation. We showed that pre-treatment with silibinin dose-dependently decreased UVB-induced apoptosis of HaCaT cells. Furthermore, we showed that silibinin treatment inhibited nuclear translocation of YAP after UVB irradiation. Molecular docking analysis and DARTS assay confirmed the direct interaction of silibinin with YAP. Silencing YAP by siRNA had no influence on the survival of HaCaT cells, whereas inhibiting classical YAP-TEAD signaling pathway by siRNA targeting TEAD1 or its pharmaceutical inhibitor verteporfin further augmented UVB-induced apoptosis, suggesting that YAP-TEAD pathway was prosurvival, which did not participate in the protective effect of silibinin. We then explored the pro-apoptotic YAP-p73 pathway. p73 was upregulated in UVB-irradiated cells, but reduced by silibinin cotreatment. The mRNA and protein levels of p73 target genes ( PML, p21 and Bax ) were all increased by UVB but decreased by silibinin co-treatment. Inhibiting p73 by using siRNA reduced UVB-induced apoptosis, suggesting that downregulation of p73 was responsible for the cytoprotective effect of silibinin. In HFFs, the upregulated YAP-p73 pathway by UVB irradiation was also suppressed by silibinin. Collectively, YAP-p73 pathway is a major cause of the death of UVB-exposed epidermal HaCaT cells and dermal HFFs. Silibinin directly inhibits YAP-p73 pathway, exerting the protective action on UVB-irradiated skin cells.

• Publisher: Springer Nature Singapore,Nature Publishing Group
• Subject: Apoptosis / BAX protein / Biomedical and Life Sciences / Biomedicine / Fibroblasts / GTP-binding protein / Humans / Immunology / Infant, Newborn / Internal Medicine / Liver diseases / Medical Microbiology / Molecular Docking Simulation / Molecular modelling / mRNA / Neonates / Nuclear transport / Pharmacology/Toxicology / RNA, Small Interfering - genetics / RNA, Small Interfering - pharmacology / Signal transduction / Silibinin / Silybin - pharmacology / Silymarin - pharmacology / siRNA / Skin diseases / Ultraviolet radiation / Vaccine / Yes-associated protein