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

Nikos Kourtis, Rana S. Moubarak, Beatriz Aranda-Orgilles, Kevin Lui, Iraz T. Aydin, Thomas Trimarchi, Farbod Darvishian, Christine Salvaggio, Judy Zhong, Kamala Bhatt, Emily I. Chen, Julide T. Celebi, Charalampos Lazaris, Aristotelis Tsirigos, Iman Osman, Eva Hernando, Iannis Aifantis

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


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 FBXW7 interacts with HSF1 through a conserved motif phosphorylated by GSK3β and ERK1. FBXW7 ubiquitylates HSF1 and loss of FBXW7 results in impaired degradation of nuclear HSF1 and defective heat-shock response attenuation. FBXW7 is either mutated or transcriptionally downregulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. FBXW7 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.

Original languageEnglish
Pages (from-to)322-332
Number of pages11
JournalNature Cell Biology
Issue number3
StatePublished - 2 Mar 2015


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