FBXW7 modulates cellular stress response and metastatic potential through ​HSF1 post-translational modification.

​Heat-shock factor 1 (​HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate ​HSF1 and thus cellular stress response are poorly understood. Here we show ...
that the ubiquitin ligase ​FBXW7α interacts with ​HSF1 through a conserved motif phosphorylated by ​GSK3β and ​ERK1. ​FBXW7α ubiquitylates ​HSF1 and loss of ​FBXW7α results in impaired degradation of nuclear ​HSF1 and defective heat-shock response attenuation. ​FBXW7α is either mutated or transcriptionally downregulated in melanoma and ​HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. ​FBXW7α deficiency and subsequent ​HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the ​HSF1 transcriptional program both in the presence of exogenous stress and in cancer.
Mesh Terms:
Amino Acid Sequence, Animals, Cell Cycle Proteins, Cell Line, Tumor, DNA-Binding Proteins, F-Box Proteins, Female, Gene Expression Regulation, Neoplastic, Genes, Reporter, Glycogen Synthase Kinase 3, HEK293 Cells, Humans, Luciferases, Melanoma, Mice, Mice, Nude, Mitogen-Activated Protein Kinase 3, Molecular Sequence Data, Neoplasm Metastasis, Neoplasm Transplantation, Protein Processing, Post-Translational, Sequence Alignment, Skin Neoplasms, Transcription Factors, Ubiquitin-Protein Ligases
Nat. Cell Biol.
Date: Mar. 01, 2015
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