Hyperoside Inhibits RNF8-mediated Nuclear Translocation of β-catenin to Repress PD-L1 Expression and Prostate Cancer

Author(s):

Jie Chen, Yi Zhao, Xiaoli Wang, Long Zang, Dengke Yin* and Song Tan*   Pages 464 - 476 ( 13 )

Abstract:

<p> Background: Hyperoside is a flavonol glycoside isolated from <i>Hypericum perforatum</i> L. that has inhibitory effects on cancer cells; however, its effects on prostate cancer (PCa) remain unclear. Therefore, we studied the anti-PCa effects of hyperoside and its underlying mechanisms <i>in vitro</i> and <i>in vivo</i>. <p> Aim: This study aimed to explore the mechanism of hyperoside in anti-PCa. <p> Methods: 3-(4,5-Dimethyl-2-Thiazolyl)-2,5-Diphenyl Tetrazolium Bromide (MTT), transwell, and flow cytometry assays were used to detect PCa cell growth, invasion, and cell apoptosis. Immunoblot analysis, immunofluorescence, immunoprecipitation, and quantitative real-time PCR (qRT-PCR) were used to analyze the antitumor mechanism of hyperoside. <p> Results: Hyperoside inhibited PCa cell growth, invasion, and cell cycle and induced cell apoptosis. Furthermore, RING finger protein 8 (RNF8), an E3 ligase that assembles K63 polyubiquitination chains, was predicted to be a direct target of hyperoside and was downregulated by hyperoside. Downregulation of RNF8 by hyperoside impeded the nuclear translocation of &#946;-catenin and disrupted the Wnt/&#946;-catenin pathway, which reduced the expression of the target genes <i>c-myc, cyclin D1</i>, and programmed death ligand 1 (<i>PD-L1</i>). Decreased PD-L1 levels contributed to induced immunity in Jurkat cells <i>in vitro</i>. Finally, <i>in vivo</i> studies demonstrated that hyperoside significantly reduced tumor size, inhibited PD-L1 and RNF8 expression, and induced apoptosis in tumor tissues of a subcutaneous mouse model. <p> Conclusion: Hyperoside exerts its anti-PCa effect by reducing RNF8 protein, inhibiting nuclear translocation of &#946;-catenin, and disrupting the Wnt/&#946;-catenin pathway, in turn reducing the expression of PD-L1 and improving Jurkat cell immunity.</p>

Keywords:

Hyperoside, prostate cancer, RING finger protein 8, &#946;-catenin pathway, K63-linked polyubiquitination, programmed death ligand 1.

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