Regulation of eIF2? by RNF4 Promotes Melanoma Tumorigenesis and Therapy Resistance.

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 (eIF2?). RNF4 binds, ubiquitinates, and stabilizes the phosphorylated eIF2? (p-eIF2?) but not activating transcription factor 4 or C/EBP homologous protein that mediates the eIF2?-dependent integrated stress response. In accordance, p-eIF2? levels were significantly elevated in high-RNF4 patient-derived melanomas. Thus, RNF4 and p-eIF2? establish a positive feed-forward loop connecting oncogenic translation and ubiquitin-dependent protein stabilization in melanoma.
Mesh Terms:
Animals, Carcinogenesis, Cell Line, Tumor, Drug Resistance, Neoplasm, Eukaryotic Initiation Factor-2, Female, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Melanoma, Mice, Mitogen-Activated Protein Kinases, Nuclear Proteins, Oncogenes, Prognosis, Protein Kinase Inhibitors, Protein Stability, Proto-Oncogene Proteins B-raf, Skin, Skin Neoplasms, Transcription Factors, Ubiquitination, Xenograft Model Antitumor Assays
J Invest Dermatol
Date: Dec. 01, 2019
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