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Heat Shock Factor 1 (HSF1) supports the ESR1 action in breast cancer (RNA-seq)

ABSTRACT: Heat shock factor 1 (HSF1) is a key regulator of transcriptional responses to proteotoxic stress. It has been recently linked to signaling of estrogen via ESR1. To study the cooperation of HSF1 and ESR1 in the transcriptional response to estrogen, we established estrogen receptor (ER)-positive breast cancer cell lines with reduced HSF1 levels using specific shRNA or CRISPR/Cas9 approach. HSF1 deficiency led to the inhibition of the mitogenic effect of estrogen in MCF7 and T47D cells. RNA-seq analyses revealed that the stimulatory effect of E2 on the transcriptome was smaller in HSF1-deficient MCF7 cells. This could partially result from the higher basal expression of E2-dependent genes in these cells as a consequence of the enhanced binding of unliganded ESR1 to chromatin, which was revealed by ChIP-seq analyses. Thus, we postulate that some fraction of ESR1 could be released from the inhibitory complex with HSP90 and gain transcriptional competence without E2-stimulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159802 | GEO | 2021/10/19

REPOSITORIES: GEO

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Heat Shock Factor 1 (HSF1) regulates ESR1 action in breast cancer

Project description:Heat shock factor 1 (HSF1) is a key regulator of transcriptional responses to proteotoxic stress. It has been recently linked to signaling of estrogen via ESR1. To study the cooperation of HSF1 and ESR1 in the transcriptional response to estrogen, we established estrogen receptor (ER)-positive breast cancer cell lines with reduced HSF1 levels using specific shRNA or CRISPR/Cas9 approach. HSF1 deficiency led to the inhibition of the mitogenic effect of estrogen in MCF7 and T47D cells. RNA-seq analyses revealed that the stimulatory effect of E2 on the transcriptome was smaller in HSF1-deficient MCF7 cells. This could partially result from the higher basal expression of E2-dependent genes in these cells as a consequence of the enhanced binding of unliganded ESR1 to chromatin, which was revealed by ChIP-seq analyses. Thus, we postulate that some fraction of ESR1 could be released from the inhibitory complex with HSP90 and gain transcriptional competence without E2-stimulation.

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Heat Shock Factor 1 (HSF1) supports the ESR1 action in breast cancer (ChIP-seq)

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Gene expression profile in MCF7 breast cancer cells after siRNA knock down of estrogen receptor alpha (ESR1)

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Project description:To improve our understanding of transcriptional regulation by ESR1 in the liver, chromatin immunoprecipitation with an antibody against ESR1 followed by high-throughput sequencing (ESR1 ChIP-Seq) was conducted in human liver samples and in hepatocytes with or without 17beta-estradiol (E2) treatment. By comparing treated and untreated hepatocytes, we identified both ligand-dependent and ligand-independent binding sites throughout the genome. Ligand-dependent binding sites include ChIP-Seq peaks that either appeared (gained peaks) or disappeared (lost peaks) upon estrogen treatment. Gained peaks occurred at the Estrogen Response Element (ERE) whereas the sites for lost peaks were instead coenriched with a variety of transcription factors. In both cases, ESR1 binding primarily occurred in enhancer regions and was associated with general liver functions, such as lipid/energy metabolism. In contrast, we also observed a subset of ESR1 sites that were maintained regardless of estrogen treatment. These ligand-independent sites mostly occurred at promoter regions and were highly enriched with several cofactor motifs.

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Gene expression profile in MCF7 breast cancer cells after siRNA knock down of estrogen receptor alpha (ESR1)

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Discovery of naturally occurring ESR1 mutations during acquisition of resistance to endocrine therapy in widely used estrogen receptor positive breast cancer cell lines [ChIP-Seq]

Project description:We report the first discovery of naturally occurring ESR1Y537C and ESR1Y537S mutations in MCF7 and MCF7 ESR1-positive cell-lines after acquisition of resistance to long-term-estrogen-deprivation (LTED) and subsequent resistance to fulvestrant (ICIR).

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Modeling the ESR1 tyrosine 537 mutation with CRISPR-Cas9 for mechanistic studies and evaluation of therapeutic approaches for metastatic breast cancer [RNA-Seq]

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Excess protein synthesis, denatured proteins or molecular crowding spontaneously induce HSF1 trimerisation and activation

Project description:Stress responses are a key feature of normal physiology and are usurped by cancer cells to ensure enhanced protein synthesis for growth, to compensate for genomic instability, and to protect cancer cells from therapy induced stress. Heat shock factor-1 (HSF1) is a major stress-response transcription factor, and its activity is markedly enhanced in cancer. Stress induces HSF1 conformational changes and post-translational modifications, leading to assembly of active HSF1 trimers that bind DNA to control target gene expression. Although the function of HSF1 in transcription is relatively well-known, the mechanisms leading to HSF1 activation and enhanced stress response in tumours are unclear. To investigate whether HSF1 is a primary sensor of proteotoxic stress in vivo, we studied the range of conditions that can cause HSF1 activation in vitro and in cells, and conditions that prevent its activation. We show that purified recombinant HSF1 adopts a stable monomeric conformation in vitro. Heat stress caused a conformational change and the assembly of HSF1 trimers. Conditions leading to protein denaturation, including heat stress, crowding, Hsp90 inhibition, or proteasome inhibition, all directly lead to HSF1 activation. In contrast, HSF1 activation in vivo is prevented by proteosynthesis inhibition, which reduces the amount of denatured proteins in the cell. These results establish that HSF1 is a direct sensor of proteotoxic stress, independent of post-translational modification, where abrupt environmental changes that cause protein denaturation simultaneously induce a conformational change in monomeric HSF1 leading to its activation. This mechanism explains the universal ability of cells to respond to proteotoxic stress and trigger a protective response when increased chaperone activities are required to restore homeostasis.

2024-08-14 | PXD037662 | Pride

Heat Shock Factor 1 (HSF1) regulates ESR1 action in breast cancer

Project description:Heat Shock Factor 1 (HSF1) regulates ESR1 action in breast cancer

| PRJNA771684 | ENA

Transcription profiling of human heat shocked HeLa cell line with siRNA knockdown of HSF1

Project description:Although HSF1 is known to play an important role in regulating the cellular response to proteotoxic stressors, little is known about the structure and function of the HSF1 signaling network under both stressed and unstressed conditions. In this study, we used a combination of chromatin immunoprecipitation (ChIP) microarray analysis and time course gene expression microarray analysis with and without siRNA-mediated inhibition of HSF1 comprehensively identify genes directly and indirectly regulated by HSF1 and examine the structure of the extended HSF1 signaling network. Correlation between promoter binding and gene expression was not significant for all genes bound by HSF1 suggesting that HSF1 binding per se is not sufficient for expression. However, the correlation with promoter binding was significant for genes identified as HSF1-regulated following siRNA knockdown allowing the identification of direct transcriptional targets of HSF1. Among promoters bound by HSF1 following heat shock, a gene ontology (GO) analysis showed significant enrichment only in categories related to protein folding. In contrast, analysis of the extended HSF1 signaling network showed enrichment in a variety of categories related to protein folding, anti-apoptosis, RNA splicing, ubiquitination and others, highlighting a complex transcriptional program directly and indirectly regulated by HSF1.,SUBMITTER_CITATION: Genome-wide analysis of human HSF1 signaling reveals a transcriptional program linked to cellular adaptation and survival Authors: Todd J. Page, Devanjan Sikder, Longlong Yang, Linda Pluta, Russell D. Wolfinger, Thomas Kodadek, and Russell S. Thomas Journal: Molecular Biosystems 2:627-639

2007-06-22 | E-GEOD-3697 | biostudies-arrayexpress

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