EZH2-Mediated PHF10 Suppression Amplifies HMGB1/NF-κB Axis That Confers Chemotherapy Resistance in Cholangiocarcinoma

J Cell Mol Med. 2025 Feb;29(3):e70363. doi: 10.1111/jcmm.70363.

Abstract

Chemoresistance represents a major threat to the treatment of human cancers, including cholangiocarcinoma (CHOL). Aberrant epigenetic events contribute most to the progression of CHOL and chemotherapy efficacy. PHF10, one subunit of SWI/SNF complex, expressed highly in tumours that correlated with tumorigenesis. However, the roles of PHF10 in CHOL remains unclear. Here, we utilised the bioinformatic analysis to reveal that PHF10 expressed lowly in CHOL samples relative to normal tissues. Functionally, we demonstrated that PHF10 deficiency enhanced cell proliferation, migration and self-renewal capacities of CHOL cells. PHF10 ablation further enhanced the chemoresistance of CHOL cells. The transcriptome analysis revealed that PHF10-KO could notably alter several oncogenic crosstalk, including the NF-kB signalling. As the top hit, HMGB1 mRNA expressions had the sharpest increase upon PHF10 deficiency. PHF10 coordinated with Setdb1 to mediate the H3K9me3 modifications on the HMGB1 promoter to suppress its expressions. Low PHF10 relied on HMGB1 to promote the progression of CHOL cells in vitro and in vivo. Furthermore, EZH2 mediated the H3K27me3 enrichment on the PHF10 promoter region that contributes to its low expressions. Lastly, the HMGB1 inhibitor (Glycyrrhizin) decreased proliferation rate of PHF10-deleted cells in vitro and in vivo. Targeting HMGB1 rendered PHF10low CHOL re-sensitive to chemotherapy. Collectively, this study demonstrated that PHF10 functions as a tumour suppressor in CHOL, and is a novel target to predict and overcome chemoresistance.

MeSH terms

  • Animals
  • Bile Duct Neoplasms* / drug therapy
  • Bile Duct Neoplasms* / genetics
  • Bile Duct Neoplasms* / metabolism
  • Bile Duct Neoplasms* / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation* / drug effects
  • Cholangiocarcinoma* / drug therapy
  • Cholangiocarcinoma* / genetics
  • Cholangiocarcinoma* / metabolism
  • Cholangiocarcinoma* / pathology
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • Drug Resistance, Neoplasm* / genetics
  • Enhancer of Zeste Homolog 2 Protein* / genetics
  • Enhancer of Zeste Homolog 2 Protein* / metabolism
  • Gene Expression Regulation, Neoplastic* / drug effects
  • HMGB1 Protein* / genetics
  • HMGB1 Protein* / metabolism
  • Humans
  • Mice
  • Mice, Nude
  • NF-kappa B* / metabolism
  • Promoter Regions, Genetic / genetics
  • Signal Transduction / drug effects

Substances

  • HMGB1 Protein
  • Enhancer of Zeste Homolog 2 Protein
  • NF-kappa B
  • EZH2 protein, human
  • HMGB1 protein, human
  • Chromosomal Proteins, Non-Histone