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.
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Acknowledgements
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.
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I.A. and N.K. designed the experiments, analysed the data and wrote the manuscript. N.K. performed the bulk of the experiments. R.S.M. performed the melanoma invasion and metastasis experiments. B.A-O. performed the FBXW7 mass-spectrometry experiment and analysed the mass-spectrometry data. I.T.A., T.T., K.L. and K.B. performed experiments. F.D. scored the primary melanoma samples. C.S. and J.Z. analysed patient data. E.I.C. analysed the mass-spectrometry data. I.O., E.H. and J.T.C. provided melanoma-related materials and contributed with ideas. A.T. and C.L. performed the analysis of genome-wide data.
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Supplementary Figure 2 Endogenously expressed FBXW7 and HSF1 interact.
(a) Native FBXW7 was immunoprecipitated (IP) from cell extracts with anti-FBXW7 antibody, followed by immunoblotting as indicated. Rabbit IgG was used as control. Arrow indicates FBXW7 in input. (b) Interaction between HSF1 and FBXW7α depends on GSK3β activity. HEK293T cells were transfected with constructs encoding FLAG tagged HSF1 and FLAG-HA tagged FBXW7α. Cells were treated with GSK3i XVI (5 μM for 8 h) or DMSO. HA-tagged FBXW7α was immunoprecipitated (IP) from cell extracts with anti-HA resin, followed by immunoblotting as indicated. (c) HEK293T cells were transfected with constructs encoding FLAG tagged HSF1 and Histidine-Myc tagged ubiquitin and infected with the indicated shRNA-encoding lentiviruses. Cells were heat shocked at 42 °C for 1 h to induce ubiquitylation. Histidine tagged proteins were immunoprecipitated from whole cell extracts with nickel (Ni)-NTA beads, followed by immunoblotting for Myc-tagged ubiquitin.
Supplementary Figure 3 Loss of FBXW7α has no effect on cytoplasmic HSF1 during recovery from exogenous stress.
(a) HCT116 WT and FBXW7 KO cells were heat shocked (42 °C for 1 h) following recovery for the indicated time. Cytoplasmic fractions were analyzed by immunoblotting as indicated. (b) HSF1 is expressed at similar levels in HCT116 WT and FBXW7 KO cells during heat shock and recovery, as revealed by real time quantitative PCR (P > 0.05 for WT or KO untreated versus heat shock and untreated versus recovery; unpaired t-test). Error bars indicate mean ± s.d., and n = 3 independent experiments. (c) HCT116 WT and FBXW7 KO cells were treated with MG132 (1 μM for 10 h) following recovery for 3 h. Cytoplasmic fractions were analysed by immunoblotting as indicated.
Supplementary Figure 4 FBXW7α deficiency results in prolonged heat-shock response activation on exposure to exogenous stress.
(a) HCT116 WT and FBXW7 KO cells were heat shocked (42 °C for 1 h) following recovery for 2 h. The expression of the heat-shock inducible HSPA6 gene was monitored by real time quantitative PCR (P < 0.001 for WT recovery versus KO recovery; two-way ANOVA; ∗∗∗P < 0.001). (b) HEK293T cells were infected with the indicated shRNA-encoding lentiviruses and heat shocked (42 °C for 1 h) following recovery for 2 h. The expression of the heat-shock inducible HSPA6 gene was monitored by real time quantitative PCR (P < 0.001 for shLUC recovery versus shFBXW7 recovery; two-way ANOVA; ∗∗∗P < 0.001). (c) HSF1 is expressed at similar levels in HCT116 WT and FBXW7 KO cells as revealed by quantitative PCR analysis (P > 0.05 for WT versus KO; unpaired t-test). Error bars indicate mean ± s.d., and n = 3 independent experiments.
Supplementary Figure 5 FBXW7α deficiency renders cells resistant to proteotoxic stress.
(a) HCT116 WT and FBXW7 KO cells were exposed for 3 days to the proteasome inhibitor MG132 (700 nM) and the HSP90 inhibitor Radicicol (200 nM). Resazurin dye reduction was assayed as a measure of relative viable cell number (P < 0.001 for WT versus KO; two-way ANOVA). (b) MEFs isolated from WT and Fbxw7 conditional knockout mice were transduced with empty or Cre expressing retroviral vector. Cytoplasmic and nuclear fractions were analysed by immunoblotting as indicated. (c) MEFs isolated from WT and Fbxw7 conditional knockout mice were transduced with empty or Cre expressing retroviral vector and scrambled or shHSF1 encoding lentiviruses as indicated and exposed for 3 days to the proteasome inhibitor MG132 (700 nM) and the HSP90 inhibitor radicicol (200 nM). Resazurin dye reduction was assayed as a measure of relative viable cell number (P < 0.001 for FBXW7flox/flox-CRE versus FBXW7flox/flox or WT, MG132 or Radicicol and P < 0.001 for FBXW7flox/flox-CRE versus FBXW7flox/flox-CRE;shHSF1, MG132 or Radicicol; two-way ANOVA). Error bars indicate mean ± s.d., and n = 3 independent experiments.
Supplementary Figure 6 FBXW7α knockdown affects specifically nuclear HSF1.
(a) 501mel cells were treated with non-coding (NC) siRNA or siRNA against FBXW7. Cytoplasmic fractions were analysed by immunoblotting as indicated. (b) HSPE1 and HSPH1 mRNA expression in 501 mel cells treated with non-coding (NC) siRNA or siRNA against FBXW7 (P < 0.001 for NC siRNA versus FBXW7 siRNA; unpaired t-test). Error bars indicate mean ± s.d., and n = 3 independent experiments. (c) 451Lu cells were treated with the BRAF inhibitor Vemurafenib (2 μM, 9 h) and MEK inhibitor Trametinib (50 nM, 9 h). Cytoplasmic fractions were analysed by immunoblotting as indicated. (d) FBXW7 deficiency results in accumulation of nuclear HSF1 during recovery from heat shock. FBXW7 wild type (SKMEL28) and FBXW7 deficient (WM39) melanoma cells transduced with empty or FBXW7α expressing retroviral vectors, were heat shocked (42 °C for 1 h), following recovery for the indicated time. Nuclear fractions were analysed by immunoblotting as indicated. (e) 451Lu, SKMEL239 and A375 cells were infected with the indicated shRNA-encoding lentiviruses. Nuclear and cytoplasmic fractions were analysed by immunoblotting as indicated. (f) 451Lu and A375 cells were infected with the indicated shRNA-encoding lentiviruses and apoptosis was measured at the indicated time points. The data represent a single experiment. (g) 451Lu and A375 cells were infected with the indicated shRNA-encoding lentiviruses and nuclear fractions were analysed as indicated.
Supplementary Figure 7 Primary tumours resected from mice flanks display markers of melanoma.
(a) Expression analysis of FBXW7 in 451Lu cells transduced with control (shLuc) or FBXW7 shRNA (P < 0.001 for shLUC versus shFBXW7, unpaired t-test). Error bars indicate mean ± s.d., and n = 3 independent experiments. (b) Representative images of Tyrosinase stained sections of subcutaneous tumours resected at termination of the experiment (scale bar, 100 μm).
Supplementary Figure 8 FBXW7 deficiency results in stabilization of nuclear HSF1 and Cyclin E in melanoma.
(a) 451Lu cells were infected with the indicated shRNA-encoding lentiviruses. Nuclear fraction was analysed by immunoblotting as indicated. (b) A375 cells were infected with the indicated shRNA-encoding lentiviruses. Nuclear fraction was analysed by immunoblotting as indicated. (c) 451Lu cells were transduced with empty or Cyclin E expressing retroviruses. Nuclear fraction was analysed by immunoblotting as indicated (left panel). One week after transduction, trans-well migration assay was performed (P > 0.05 for 451Lu empty versus CCNE1; n = 10 fields per biological replicate; 4 biological replicates; unpaired t-test). Error bars indicate mean ± s.d. (d) 451Lu cells were infected with the indicated shRNA-encoding lentiviruses. One week after transduction, trans-well invasion assay was performed (P < 0.05 for 451Lu shLUC versus shFBXW7; n = 10 fields per biological replicate; 4 biological replicates; unpaired t-test). Error bars indicate mean ± s.d. (e) Expression levels of FBXW7, HSF1 and CCNE1 on infection with the corresponding shRNA-encoding lentiviruses (P < 0.001 for Scrambled versus shRNA for FBXW7 or HSF1 or CCNE1; unpaired t-test). Error bars indicate mean ± s.d., and n = 3 independent experiments. (f) Schematic representation of the heat-shock response pathway regulation during recovery from exogenous stress (top) and in cancer context (bottom).
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Kourtis, N., Moubarak, R., Aranda-Orgilles, B. et al. FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification. Nat Cell Biol 17, 322–332 (2015). https://doi.org/10.1038/ncb3121
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DOI: https://doi.org/10.1038/ncb3121
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