Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-κB Pathway in Melanoma

Clin Cancer Res. 2017 Aug 15;23(16):4831-4842. doi: 10.1158/1078-0432.CCR-17-0146. Epub 2017 Apr 7.


Purpose: Abnormal activation of the NF-κB pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-κB activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of the NF-κB pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma.Experimental Design: The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue microarrays; n = 137, JWCI cohort; n = 40) and The Cancer Genome Atlas database (TCGA cohort, n = 370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-κB, and the epigenetic regulations of KPC1, including DNA methylation and miRNA expression.Results: We verified that KPC1 suppresses melanoma proliferation by processing NF-κB1 p105 into p50, thereby modulating NF-κB target gene expression. Concordantly, KPC1 expression was downregulated in American Joint Committee on Cancer stage IV melanoma compared with early stages (stage I/II P = 0.013, stage III P = 0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma (n = 137; HR 1.810; P = 0.006). Furthermore, our data showed that high miR-155-5p expression, which is controlled by DNA methylation at its promoter region (TCGA; Pearson's r -0.455; P < 0.001), is significantly associated with KPC1 downregulation (JWCI; P = 0.028, TCGA; P = 0.003).Conclusions: This study revealed novel epigenetic regulation of KPC1 associated with NF-κB pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets. Clin Cancer Res; 23(16); 4831-42. ©2017 AACR.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cohort Studies
  • DNA Methylation
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Melanoma / pathology
  • MicroRNAs / genetics
  • NF-kappa B / genetics*
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic / genetics
  • RNA Interference
  • Signal Transduction / genetics
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism


  • MIRN155 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • RNF123 protein, human
  • Ubiquitin-Protein Ligases