@article{Song2025, 
author = {Xingchao Song and Qiuyu Song and Xiao Ma and Anzhi Xu and Chunyan Tian},
title = {MINDY1 Induces PD-L1 Deubiquitination to Promote Immune Escape in Hepatocellular Carcinoma by the Wnt/β-Catenin Pathway},
year = {2025},
journal = {Oncology Research},
volume = {33},
number = {11},
pages = {3583-3603},
keywords = {Hepatocellular carcinoma, motif interacting with ubiquitin-containing novel DUB family-1, Wnt/β-catenin, programmed death-ligand 1, immune escape},
url = {https://www.sciopen.com/article/10.32604/or.2025.067638},
doi = {10.32604/or.2025.067638},
abstract = {BackgroundMotif interacting with ubiquitin-containing novel DUB family-1 (MINDY1) could enhance the stability of programmed death-ligand 1 (PD-L1). The study aimed to investigate whether MINDY1 regulates the immune escape of hepatocellular carcinoma (HCC) mediated by PD-L1.MethodsMINDY1 and PD-L1 levels were detected through Western blot. The link between MINDY1 and PD-L1 was validated using the co-immunoprecipitation assay. The malignant biology of HCC cells was assessed through Cell Counting Kit-8, Carboxyfluorescein Succinimidyl Ester staining, transwell, and wound healing assay. CD8+ T cells were isolated and then co-cultured with HCC cells. Enzyme-linked immunosorbent Assay kits detected CD8+ T cytokine content. CD8+ T cell activation markers, PD-L1 ubiquitination levels, and Wnt/β-catenin pathway-associated protein levels were detected through Western blot. A HCC nude mouse model was developed, Ki-67 positivity and CD8+ T-cell infiltration were assessed through pathological staining and flow cytometry.ResultsMINDY1 and PD-L1 levels were elevated in HCC. Overexpression of MINDY1 increased migrating and invading cells, elevated cell viability, and decreased apoptosis in HCC cells, leading to PD-L1 deubiquitination. Knockdown of MINDY1 reversed all of these indicators. Co-culturing with HCC cells overexpressing MINDY1 resulted in decreased proliferative capacity and cytotoxicity of CD8+ T cells, increased apoptosis, and decreased levels of cytokines and activation markers in CD8+ T cells. MINDY1 triggered Wnt/β-catenin pathway, Wnt activators further promoted PD-L1 deubiquitination and suppressed CD8+ T cell activation. MINDY1 overexpression increased PD-L1 and Ki67 positivity level in HCC tumors, suppressed CD8+ T-cell infiltration.ConclusionMINDY1 promotes PD-L1 deubiquitination and inhibits CD8+ T cell activation by stimulating the Wnt/β-catenin pathway, consequently promoting HCC tumor immune escape.}
}