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

doi:10.1038/ncb3121

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

Division of Dermatology

Research output: Contribution to journal › Article › peer-review

118 Scopus citations

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 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 language	English
Pages (from-to)	322-332
Number of pages	11
Journal	Nature Cell Biology
Volume	17
Issue number	3
DOIs	https://doi.org/10.1038/ncb3121
State	Published - Mar 2 2015

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Kourtis, N., Moubarak, R. S., Aranda-Orgilles, B., Lui, K., Aydin, I. T., Trimarchi, T., Darvishian, F., Salvaggio, C., Zhong, J., Bhatt, K., Chen, E. I., Celebi, J. T., Lazaris, C., Tsirigos, A., Osman, I., Hernando, E., & Aifantis, I. (2015). FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification. Nature Cell Biology, 17(3), 322-332. https://doi.org/10.1038/ncb3121

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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 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.",

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

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year = "2015",

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doi = "10.1038/ncb3121",

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Kourtis, N, Moubarak, RS, Aranda-Orgilles, B, Lui, K, Aydin, IT, Trimarchi, T, Darvishian, F, Salvaggio, C, Zhong, J, Bhatt, K, Chen, EI, Celebi, JT, Lazaris, C, Tsirigos, A, Osman, I, Hernando, E & Aifantis, I 2015, 'FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification', Nature Cell Biology, vol. 17, no. 3, pp. 322-332. https://doi.org/10.1038/ncb3121

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AU - Kourtis, Nikos

AU - Moubarak, Rana S.

AU - Aranda-Orgilles, Beatriz

AU - Lui, Kevin

AU - Aydin, Iraz T.

AU - Trimarchi, Thomas

AU - Darvishian, Farbod

AU - Salvaggio, Christine

AU - Zhong, Judy

AU - Bhatt, Kamala

AU - Chen, Emily I.

AU - Celebi, Julide T.

AU - Lazaris, Charalampos

AU - Tsirigos, Aristotelis

AU - Osman, Iman

AU - Hernando, Eva

AU - Aifantis, Iannis

PY - 2015/3/2

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N2 - 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.

AB - 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.

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

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