1. Regulation of eIF2α by RNF4 Promotes Melanoma Tumorigenesis and Therapy Resistance
- Author
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Tongwu Zhang, Yongmei Feng, Chaim Kahana, Ze'ev Ronai, Harriet M. Kluger, Avital Oknin Vaisman, Emily Avitan-Hersh, Kevin M. Brown, Ikrame Lazar, Saeed Sheikh Khalil, Amir Orian, Yaniv Zohar, Eytan Ruppin, Joo Sang Lee, Yamen Abu Ahmad, and Yulia Feiler
- Subjects
Proto-Oncogene Proteins B-raf ,0301 basic medicine ,Skin Neoplasms ,Carcinogenesis ,medicine.medical_treatment ,Eukaryotic Initiation Factor-2 ,Activating transcription factor ,Kaplan-Meier Estimate ,Dermatology ,Activating Transcription Factor 4 ,Biochemistry ,Article ,Targeted therapy ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Melanoma ,Protein Kinase Inhibitors ,Molecular Biology ,Skin ,biology ,Protein Stability ,ATF4 ,Ubiquitination ,Nuclear Proteins ,Oncogenes ,Cell Biology ,Prognosis ,medicine.disease ,Xenograft Model Antitumor Assays ,Ubiquitin ligase ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Proteostasis ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Female ,Mitogen-Activated Protein Kinases ,Protein stabilization ,Transcription Factors - Abstract
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.
- Published
- 2020