Regulation of eIF2α by RNF4 Promotes Melanoma Tumorigenesis and Therapy Resistance

J Invest Dermatol. 2020 Dec;140(12):2466-2477. doi: 10.1016/j.jid.2020.04.008. Epub 2020 Apr 29.


Among the hallmarks of melanoma are impaired proteostasis and rapid development of resistance to targeted therapy that represent a major clinical challenge. However, the molecular machinery that links these processes is unknown. Here we describe that by stabilizing key melanoma oncoproteins, the ubiquitin ligase RNF4 promotes tumorigenesis and confers resistance to targeted therapy in melanoma cells, xenograft mouse models, and patient samples. In patients, RNF4 protein and mRNA levels correlate with poor prognosis and with resistance to MAPK inhibitors. Remarkably, RNF4 tumorigenic properties, including therapy resistance, require the translation initiation factor initiation elongation factor alpha (eIF2α). RNF4 binds, ubiquitinates, and stabilizes the phosphorylated eIF2α (p-eIF2α) but not activating transcription factor 4 or C/EBP homologous protein that mediates the eIF2α-dependent integrated stress response. In accordance, p-eIF2α levels were significantly elevated in high-RNF4 patient-derived melanomas. Thus, RNF4 and p-eIF2α establish a positive feed-forward loop connecting oncogenic translation and ubiquitin-dependent protein stabilization in melanoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • Eukaryotic Initiation Factor-2 / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • Melanoma / drug therapy
  • Melanoma / genetics*
  • Melanoma / mortality
  • Melanoma / pathology
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Nuclear Proteins / metabolism*
  • Oncogenes / genetics
  • Prognosis
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Stability
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Skin / pathology
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / mortality
  • Skin Neoplasms / pathology
  • Transcription Factors / metabolism*
  • Ubiquitination / genetics
  • Xenograft Model Antitumor Assays


  • EIF2S1 protein, human
  • Eukaryotic Initiation Factor-2
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • RNF4 protein, human
  • Transcription Factors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinases