title: FBXW7 modulates cellular stress response and metastatic potential through ​HSF1 post-translational modification.
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.
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.|NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Nikos
authors.initials: N
authors.lastname: Kourtis
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.|Interdisciplinary Melanoma Cooperative Group, NYU Cancer Institute, New York, NY 10016, USA.
authors.forename: Rana S
authors.initials: RS
authors.lastname: Moubarak
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.|NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Aranda-Orgilles
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, NYU Cancer Institute, New York, NY 10016, USA.|Ronald O. Perelman Department of Dermatology, NYU School of Medicine, New York, New York, NY 10016, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lui
authors.affiliation: Departments of Pathology and Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Iraz T
authors.initials: IT
authors.lastname: Aydin
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.|NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Trimarchi
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.|Interdisciplinary Melanoma Cooperative Group, NYU Cancer Institute, New York, NY 10016, USA.
authors.forename: Farbod
authors.initials: F
authors.lastname: Darvishian
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, NYU Cancer Institute, New York, NY 10016, USA.|Ronald O. Perelman Department of Dermatology, NYU School of Medicine, New York, New York, NY 10016, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Salvaggio
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, NYU Cancer Institute, New York, NY 10016, USA.|Department of Population Health, New York University School of Medicine, New York, New York.|Department of Environmental Medicine, New York University School of Medicine, New York, New York.
authors.forename: Judy
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.|NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Kamala
authors.initials: K
authors.lastname: Bhatt
authors.affiliation: The Herbert Irving Comprehensive Cancer Center, Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Emily I
authors.initials: EI
authors.lastname: Chen
authors.affiliation: Departments of Pathology and Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Julide T
authors.initials: JT
authors.lastname: Celebi
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.|NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.|Center for Health Informatics and Bioinformatics, NYU School of Medicine, NY 10016, USA.
authors.forename: Charalampos
authors.initials: C
authors.lastname: Lazaris
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.|Center for Health Informatics and Bioinformatics, NYU School of Medicine, NY 10016, USA.
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Tsirigos
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, NYU Cancer Institute, New York, NY 10016, USA.|Ronald O. Perelman Department of Dermatology, NYU School of Medicine, New York, New York, NY 10016, USA.
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.|Interdisciplinary Melanoma Cooperative Group, NYU Cancer Institute, New York, NY 10016, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Hernando
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.|NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011499:Protein Processing, Post-Translational; D016415:Sequence Alignment; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; D008156:Luciferases; D044767:Ubiquitin-Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3