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Tight coordination of protein translation and heat shock factor 1 activation supports the anabolic malignant state [ChIP-Seq]

ABSTRACT: A unifying characteristic of aggressive cancers is a profound anabolic shift in metabolism to enable sustained proliferation and biomass expansion. The ribosome is centrally situated to sense metabolic states but whether it impacts systems that promote cellular survival is unknown. Here, through integrated chemical-genetic analyses, we find that a dominant transcriptional effect of blocking protein translation in cancer cells is complete inactivation of heat shock factor 1 (HSF1), a multifaceted transcriptional regulator of the heat-shock response and many other cellular processes essential for tumorigenesis. Translational flux through the ribosome reshapes the transcriptional landscape and links the fundamental anabolic processes of protein production and energy metabolism with HSF1 activity. Targeting this link deprives cancer cells of their energy and chaperone armamentarium thereby rendering the malignant phenotype unsustainable.

ORGANISM(S): Homo sapiens

PROVIDER: GSE45852 | GEO | 2013/07/21

SECONDARY ACCESSION(S): PRJNA196591

REPOSITORIES: GEO

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Tight coordination of protein translation and heat shock factor 1 activation supports the anabolic malignant state [ChIP-Seq]

Project description:A unifying characteristic of aggressive cancers is a profound anabolic shift in metabolism to enable sustained proliferation and biomass expansion. The ribosome is centrally situated to sense metabolic states but whether it impacts systems that promote cellular survival is unknown. Here, through integrated chemical-genetic analyses, we find that a dominant transcriptional effect of blocking protein translation in cancer cells is complete inactivation of heat shock factor 1 (HSF1), a multifaceted transcriptional regulator of the heat-shock response and many other cellular processes essential for tumorigenesis. Translational flux through the ribosome reshapes the transcriptional landscape and links the fundamental anabolic processes of protein production and energy metabolism with HSF1 activity. Targeting this link deprives cancer cells of their energy and chaperone armamentarium thereby rendering the malignant phenotype unsustainable. We used ChIP-Seq to examine affect of rocaglates and cycloheximide on HSF1 genomic occupancy in MCF7 and M0-91 cancer cells.

2013-07-21 | E-GEOD-45852 | biostudies-arrayexpress

Tight coordination of protein translation and heat shock factor 1 activation supports the anabolic malignant state [Gene Expression Data]

Project description:A unifying characteristic of aggressive cancers is a profound anabolic shift in metabolism to enable sustained proliferation and biomass expansion. The ribosome is centrally situated to sense metabolic states but whether it impacts systems that promote cellular survival is unknown. Here, through integrated chemical-genetic analyses, we find that a dominant transcriptional effect of blocking protein translation in cancer cells is complete inactivation of heat shock factor 1 (HSF1), a multifaceted transcriptional regulator of the heat-shock response and many other cellular processes essential for tumorigenesis. Translational flux through the ribosome reshapes the transcriptional landscape and links the fundamental anabolic processes of protein production and energy metabolism with HSF1 activity. Targeting this link deprives cancer cells of their energy and chaperone armamentarium thereby rendering the malignant phenotype unsustainable. Gene Expression Data We used microarrays to examine affect of rocaglates on gene expression in cancer cell lines. MCF7 breast cancer cells were treated with either 200 nM Rocaglamide A or DMSO, as a control. Two biological replicates for all samples.

2013-07-21 | E-GEOD-45851 | biostudies-arrayexpress

Tight coordination of protein translation and heat shock factor 1 activation supports the anabolic malignant state [Gene Expression Data]

2013-07-21 | GSE45851 | GEO

HSF2 cooperates with HSF1 to drive a transcriptional program critical for the malignant state

Project description:Heat shock factor 1 (HSF1) is well known for its role in the heat shock response (HSR), where it drives a transcriptional program comprising heat shock protein (HSP) genes, and in tumorigenesis, where it drives a program comprising HSPs and many non-canonical target genes that support malignancy. Here, we find that HSF2, an HSF1 paralog with no significant role in the HSR, physically and functionally interacts with HSF1 across diverse types of cancer. HSF1 and HSF2 have strikingly similar chromatin occupancy and regulate a common set of genes which include both HSPs and non-canonical transcriptional targets with roles critical in supporting malignancy. Loss of either HSF1 or HSF2 results in a dysregulated response to nutrient stresses in vitro and reduced tumor progression in cancer cell line xenografts. Taken together, these findings establish HSF2 as a critical cofactor of HSF1 in driving a cancer cell transcriptional program to support the anabolic malignant state.

2022-03-15 | GSE194098 | GEO

Genetic and Epigenetic Determinants Establish a Continuum of Hsf1 Occupancy and Activity Across the Yeast Genome

Project description:We performed ChIP-seq of Hsf1 under non heat shock, 5-minute heat shock and 120 minute heat shock conditions. We used the conditional chemical genetics approach known as “anchor away” (AA) to rapidly inactivate Hsf1. We coupled Hsf1-AA to and nascent RNA seq (NAC)-seq to define the genes whose expression depends on Hsf1 during heat shock.

2018-07-26 | GSE117653 | GEO

Identification of HSF1- target genes involved in thermal stress in the Pacific oyster Crassostrea gigas by ChIP-seq

Project description:The Pacific oyster Crassostrea gigas, a commercially important species inhabiting the intertidal zone, can tolerate temperature fluctuations. Heat shock transcription factor 1 (HSF1) plays an important role in the process of resistance of thermal stress. However, HSF1 has not been fully characterized in the Pacific oyster. C. gigas with an expansion of heat shock protein (HSP) 70. In this study, we analyzed genes regulated by HSF1 in response to heat shock by Chromatin immunoprecipitation followed sequencing (ChIP-seq), determined the expression patterns of target genes by qRT-PCR, and validated the regulatory relationship between one HSP70 and HSF1. We found 916 peaks corresponding to specific binding sites of HSF1, and peaks were annotated to nearest genes. In Gene Ontology analysis, HSF1 target genes was related to signal transduction, energy production, and response to biotic stimulus. Four HSP70 genes, two HSP40 genes, and one small HSP gene exhibited binding to HSF1. One HSP70 with a binding site in the promoter region was validated to be regulated by HSF1 under heat shock. These results provide a basis for future studies aimed at determining the mechanisms underlying thermal tolerance and provide insights into gene regulation in the Pacific oyster.

2020-10-16 | GSE138959 | GEO

Sivery2016 - A mammalian heat shock response model

Project description:Environmental stress, such as oxidative or heat stress, induces the activation of the heat shock response (HSR) and leads to an increase in the heat shock proteins (HSPs) level. These HSPs act as molecular chaperones to maintain cellular proteostasis. Controlled by highly intricate regulatory mechanisms, having stress-induced activation and feedback regulations with multiple partners, the HSR is still incompletely understood. In this context, we propose a minimal molecular model for the gene regulatory network of the HSR that reproduces quantitatively different heat shock experiments both on heat shock factor 1 (HSF1) and HSPs activities. This model, which is based on chemical kinetics laws, is kept with a low dimensionality without altering the biological interpretation of the model dynamics. This simplistic model highlights the titration of HSF1 by chaperones as the guiding line of the network. Moreover, by a steady states analysis of the network, three different temperature stress regimes appear: normal, acute, and chronic, where normal stress corresponds to pseudo thermal adaption. The protein triage that governs the fate of damaged proteins or the different stress regimes are consequences of the titration mechanism. The simplicity of the present model is of interest in order to study detailed modelling of cross regulation between the HSR and other major genetic networks like the cell cycle or the circadian clock. Sivéry, A., Courtade, E., Thommen, Q. (2016). A minimal titration model of the mammalian dynamical heat shock response. Physical biology, 13(6), 066008.

2022-01-25 | MODEL2201210001 | BioModels

HSF1 mediated Gene regulation in T cells at normal (37C) and febrile (40C) temperatures

Project description:HSF1 is a major transcriptional regulator of heat shock responses. Many cells activate HSF1 in response to heat shock temperatures (>42oC) and other cellular stress causing agents. Unlike other cell types, T cells activate HSF1 in response to T cell activation or when exposed to febrile (40oC) temperatures, suggesting a role for HSF1 beyond the heat-shock response. We used microarray analysis and HSF1 knock-out mice to study the HSF1 mediated gene regulation in activated T cells under normal and fever temperatures.

2012-09-20 | GSE41005 | GEO

Transriptional profiling upon heat shock and recovery in cells deficient for FBXW7 and their wild type counterpart.

Project description:FBXW7 modulates stress response by post-translational modification of HSF1 HSF1 orchestrates the heat-shock response upon exposure to heat stress and activates a transcriptional program vital for cancer cells. Genes positively regulated by HSF1 show increeased expression during heat shock while their expression is reduced during recovery. Genes negatively regulated by HSF1 show the opposite pattern. In this study we utilized the HCT116 FBXW7 KO colon cell line and its wild type counterpart to monitor gene expression changes during heat shock (42oC, 1 hour) and recovery (37oC for 2 hours post heat shock) using RNA sequencing. These results revealed that the heat-shock response pathway is prolonged in cells deficient for FBXW7.

2015-02-20 | GSE57397 | GEO

Hijacking of stress response machinery by oncogenes in acute leukaemia [ChIP-seq]

Project description:HSF1 orchestrates the heat shock response pathway. This pathway is co-opted in cancer and provides critical stress relief from oncogenic stress. HSF1 has a diverse occupancy signature depending on the cell type. In this study, we performed HSF1 ChIP-seq analysis using the human T-ALL cell line CUTLL1 and P12. These results revealed the HSF1 chromatin binding signature in CUTLL1 and P12 cells. MYC is a driving oncogene in T-ALL. The non-oncogene addiction pathways that act downstream of this transcription factor to support anabolic pathways are not well-understood. For this reason, we performed MYC ChIP-seq analysis using the human T-ALL cell line CUTLL1. These results revealed that HSF1 and HSF1 targets are included in the MYC binding signature.

2018-03-20 | GSE90716 | GEO

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