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

92 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

@article{1a434ece0a0b4c6f8bf9ece6863dcae2,

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",

note = "Funding Information: We would like to thank the members of the Aifantis laboratory for helpful discussions, B. Vogelstein (Johns Hopkins University, USA) for the HCT116 cell lines and M. Pagano (New York University School of Medicine, USA) and L. Busino (University of Pennsylvania, USA) for helpful discussions and for plasmids. The Aifantis laboratory is supported by the National Institutes of Health (1R01CA169784-02, 1R01CA133379-06, 1R01CA105129-08, 1R01CA149655-04, 5R01CA173636-03, 1R24OD018339-01), the William Lawrence and Blanche Hughes Foundation, The Leukemia & Lymphoma Society (TRP no. 6340-11, LLS no. 6373-13), The Chemotherapy Foundation, The V Foundation for Cancer Research, Alex{\textquoteright}s Lemonade Stand Foundation for Childhood Cancer and St. Baldrick{\textquoteright}s Cancer Research Foundation. FBXW7 work has also been supported by a NY STEM grant (CO28130). The Hernando Laboratory is supported by the NIH/NCI (1R01CA155234, 1R01CA163891-01A1) and the Department of Defense (DOD) Collaborative Award (CA093471). B.A-O. is supported by Deutsche Jose Carreras Leukaemie Stiftung. N.K. is supported by a European Molecular Biology Organization (EMBO) Long Term Fellowship and a Human Frontiers Science Program (HFSP) Long Term Fellowship. I.A. is a Howard Hughes Medical Institute Early Career Scientist. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = mar,

day = "2",

doi = "10.1038/ncb3121",

language = "English",

volume = "17",

pages = "322--332",

journal = "Nature Cell Biology",

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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

TY - JOUR

T1 - FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification

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

N1 - Funding Information: We would like to thank the members of the Aifantis laboratory for helpful discussions, B. Vogelstein (Johns Hopkins University, USA) for the HCT116 cell lines and M. Pagano (New York University School of Medicine, USA) and L. Busino (University of Pennsylvania, USA) for helpful discussions and for plasmids. The Aifantis laboratory is supported by the National Institutes of Health (1R01CA169784-02, 1R01CA133379-06, 1R01CA105129-08, 1R01CA149655-04, 5R01CA173636-03, 1R24OD018339-01), the William Lawrence and Blanche Hughes Foundation, The Leukemia & Lymphoma Society (TRP no. 6340-11, LLS no. 6373-13), The Chemotherapy Foundation, The V Foundation for Cancer Research, Alex’s Lemonade Stand Foundation for Childhood Cancer and St. Baldrick’s Cancer Research Foundation. FBXW7 work has also been supported by a NY STEM grant (CO28130). The Hernando Laboratory is supported by the NIH/NCI (1R01CA155234, 1R01CA163891-01A1) and the Department of Defense (DOD) Collaborative Award (CA093471). B.A-O. is supported by Deutsche Jose Carreras Leukaemie Stiftung. N.K. is supported by a European Molecular Biology Organization (EMBO) Long Term Fellowship and a Human Frontiers Science Program (HFSP) Long Term Fellowship. I.A. is a Howard Hughes Medical Institute Early Career Scientist. Publisher Copyright: © 2015 Macmillan Publishers Limited.

PY - 2015/3/2

Y1 - 2015/3/2

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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U2 - 10.1038/ncb3121

DO - 10.1038/ncb3121

M3 - Article

C2 - 25720964

AN - SCOPUS:84923796552

SN - 1465-7392

VL - 17

SP - 322

EP - 332

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 3

ER -

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

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