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Nat Cell Biol. 2015 Mar;17(3):322-332. doi: 10.1038/ncb3121.

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

Author information

1
Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
2
NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
3
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
4
Interdisciplinary Melanoma Cooperative Group, NYU Cancer Institute, New York, NY 10016, USA.
5
Ronald O. Perelman Department of Dermatology, NYU School of Medicine, New York, New York, NY 10016, USA.
6
Departments of Pathology and Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7
Department of Population Health, New York University School of Medicine, New York, New York.
8
Department of Environmental Medicine, New York University School of Medicine, New York, New York.
9
The Herbert Irving Comprehensive Cancer Center, Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA.
10
Center for Health Informatics and Bioinformatics, NYU School of Medicine, NY 10016, USA.
#
Contributed equally

Abstract

​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.

PMID:
25720964
PMCID:
PMC4401662
DOI:
10.1038/ncb3121
[Indexed for MEDLINE]
Free PMC Article

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