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

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 - Nat. Cell Biol. (2015)

Bottom Line: ​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.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.

View Article: PubMed Central - PubMed

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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HSF1 drives a metastatic-supportive transcriptional program that is affected by FBXW7 expression levels(a) Genomic distribution of the regions of HSF1 occupancy (promoter, intragenic or intergenic). GSEA enrichment plot showing significant enrichment of the top 600 HSF1 targets for genes linked to metastasis in melanoma (Normalized Enrichment Score, NES=1.72; P=0.006). (b) Representative ChIP-Seq tracks of HSF1 metastasis-related targets. The scale corresponds to Reads Per Million (RPM). (c) mRNA expression analysis of HSF1 metastasis-related targets upon depletion of FBXW7 (P<0.01 for shLUC versus shFBXW7 for ADAM17 or ADAM22 or MTHFD2 and P<0.001 for shLUC versus shFBXW7 for HMGB1 or ITGB3BP; unpaired t-test). Error bars indicate mean ± SD, and n=3 independent experiments.
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Figure 7: HSF1 drives a metastatic-supportive transcriptional program that is affected by FBXW7 expression levels(a) Genomic distribution of the regions of HSF1 occupancy (promoter, intragenic or intergenic). GSEA enrichment plot showing significant enrichment of the top 600 HSF1 targets for genes linked to metastasis in melanoma (Normalized Enrichment Score, NES=1.72; P=0.006). (b) Representative ChIP-Seq tracks of HSF1 metastasis-related targets. The scale corresponds to Reads Per Million (RPM). (c) mRNA expression analysis of HSF1 metastasis-related targets upon depletion of FBXW7 (P<0.01 for shLUC versus shFBXW7 for ADAM17 or ADAM22 or MTHFD2 and P<0.001 for shLUC versus shFBXW7 for HMGB1 or ITGB3BP; unpaired t-test). Error bars indicate mean ± SD, and n=3 independent experiments.

Mentions: To gain insights into the molecular basis of HSF1 metastasis-supportive transcriptional program, we performed HSF1 ChIP-Seq analysis using the 451Lu melanoma cells. Initial analysis suggested a preference for promoter binding (Fig. 7a). Gene enrichment analysis (GSEA) of HSF1 targets using publicly available data44 revealed significant enrichment for gene sets containing genes significantly altered in metastatic relative to primary melanomas (Fig. 7a, b). To better focus on bona fide melanoma metastasis regulators, we exploited recent studies that described a number of pro-invasive and oncogenic genes in melanoma43. Strikingly, our analysis revealed that several of these invasion/metastasis drivers are directly bound by HSF1 (Fig. 7b; MTHFD2, HMGB1 and ITGB3BP). We hypothesized that nuclear HSF1 accumulation upon FBXW7 knockdown may result in upregulation of the melanoma transcriptional program. To test this hypothesis, we monitored the expression of selected metastasis-related HSF1 targets, upon FBXW7 knockdown. FBXW7 silencing resulted in significant upregulation of such HSF1 targets (Fig. 7c). Based on these findings, we suggest that HSF1 orchestrates a metastasis-supportive transcriptional program that is bolstered upon nuclear accumulation due to FBXW7 deficiency/mutation.


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

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 - Nat. Cell Biol. (2015)

HSF1 drives a metastatic-supportive transcriptional program that is affected by FBXW7 expression levels(a) Genomic distribution of the regions of HSF1 occupancy (promoter, intragenic or intergenic). GSEA enrichment plot showing significant enrichment of the top 600 HSF1 targets for genes linked to metastasis in melanoma (Normalized Enrichment Score, NES=1.72; P=0.006). (b) Representative ChIP-Seq tracks of HSF1 metastasis-related targets. The scale corresponds to Reads Per Million (RPM). (c) mRNA expression analysis of HSF1 metastasis-related targets upon depletion of FBXW7 (P<0.01 for shLUC versus shFBXW7 for ADAM17 or ADAM22 or MTHFD2 and P<0.001 for shLUC versus shFBXW7 for HMGB1 or ITGB3BP; unpaired t-test). Error bars indicate mean ± SD, and n=3 independent experiments.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4401662&req=5

Figure 7: HSF1 drives a metastatic-supportive transcriptional program that is affected by FBXW7 expression levels(a) Genomic distribution of the regions of HSF1 occupancy (promoter, intragenic or intergenic). GSEA enrichment plot showing significant enrichment of the top 600 HSF1 targets for genes linked to metastasis in melanoma (Normalized Enrichment Score, NES=1.72; P=0.006). (b) Representative ChIP-Seq tracks of HSF1 metastasis-related targets. The scale corresponds to Reads Per Million (RPM). (c) mRNA expression analysis of HSF1 metastasis-related targets upon depletion of FBXW7 (P<0.01 for shLUC versus shFBXW7 for ADAM17 or ADAM22 or MTHFD2 and P<0.001 for shLUC versus shFBXW7 for HMGB1 or ITGB3BP; unpaired t-test). Error bars indicate mean ± SD, and n=3 independent experiments.
Mentions: To gain insights into the molecular basis of HSF1 metastasis-supportive transcriptional program, we performed HSF1 ChIP-Seq analysis using the 451Lu melanoma cells. Initial analysis suggested a preference for promoter binding (Fig. 7a). Gene enrichment analysis (GSEA) of HSF1 targets using publicly available data44 revealed significant enrichment for gene sets containing genes significantly altered in metastatic relative to primary melanomas (Fig. 7a, b). To better focus on bona fide melanoma metastasis regulators, we exploited recent studies that described a number of pro-invasive and oncogenic genes in melanoma43. Strikingly, our analysis revealed that several of these invasion/metastasis drivers are directly bound by HSF1 (Fig. 7b; MTHFD2, HMGB1 and ITGB3BP). We hypothesized that nuclear HSF1 accumulation upon FBXW7 knockdown may result in upregulation of the melanoma transcriptional program. To test this hypothesis, we monitored the expression of selected metastasis-related HSF1 targets, upon FBXW7 knockdown. FBXW7 silencing resulted in significant upregulation of such HSF1 targets (Fig. 7c). Based on these findings, we suggest that HSF1 orchestrates a metastasis-supportive transcriptional program that is bolstered upon nuclear accumulation due to FBXW7 deficiency/mutation.

Bottom Line: ​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.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.

View Article: PubMed Central - PubMed

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.

Show MeSH
Related in: MedlinePlus