HSF2 drives breast cancer progression by acting as a stage-specific switch between proliferation and invasion
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PROVIDER: PRJNA868701 | ENA |
REPOSITORIES: ENA
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Project description:Breast cancer is hallmarked by phenotypic transitions enabling abnormal cell proliferation and invasion. The stress-protective transcription factor heat shock factor 2 (HSF2) is associated with cancer, but its function in breast carcinogenesis remains poorly understood. Analysis of human breast tumor samples and mouse in vivo xenografts uncovered that HSF2 expression and activity undergo dynamic changes as a function of tumor progression. HSF2 expression, nuclear localization, and co-expression with the proliferation marker Ki67 are increased in ductal carcinoma in situ (DCIS), suggesting that HSF2 designates hyperplastic cells underlying tumor expansion. In mouse xenografts, HSF2 localization switches from nuclear to cytoplasmic upon DCIS-to-invasive transition. Using cell-based models, we identify canonical TGF-β signaling as the molecular mechanism regulating HSF2. TGF-β-mediated downregulation of HSF2 allowed acquisition of an invasive cell phenotype, which was counteracted by ectopic HSF2. Altogether, we propose that HSF2 acts as a stage-specific switch between proliferation and invasion in breast cancer.
2025-07-23 | GSE211020 | GEO
Project description:Heat-shock factors (HSFs) are key transcriptional regulators in cell survival. Although HSF1 has been identified as a driver of carcinogenesis, HSF2 has not been explored in malignancies. Here, we report that HSF2 suppresses tumor invasion of prostate cancer (PrCa). In three-dimensional organotypic cultures and the in vivo xenograft chorioallantoic membrane model HSF2 knockdown perturbs organoid differentiation and promotes invasiveness. Gene expression profiling together with functional studies demonstrated that the molecular mechanism underlying the effect on tumor progression originates from HSF2 steering the switch between acinar morphogenesis and invasion. This is achieved by the regulation of genes connected to, for example, GTPase activity, cell adhesion, extracellular matrix and actin cytoskeleton dynamics. Importantly, low HSF2 expression correlates with high Gleason score, metastasis and poor survival of PrCa patients, highlighting the clinical relevance of our findings. Finally, the study was expanded beyond PrCa, revealing that the expression of HSF2 is decreased in a wide range of cancer types. This study provides the first evidence for HSF2 acting as a suppressor of invasion in human malignancies.
2013-12-23 | GSE48672 | GEO
Project description:Prostate cancer (PrCa) is one of the most common malignancies in Western countries. However, the pathways that promote invasion, especially in late-stage castration-resistant PrCa (CRPC), are poorly understood. Heat shock factors (HSFs) are transcriptional regulators essential for cell survival upon proteotoxic stress, and HSF1 is also identified as a driver of oncogenesis. Here, our aim was to elucidate the molecular mechanisms that contribute to CRPC and invasion. In silico analyses showed that high HSF1 expression levels correlate with poor survival and high Gleason score in PrCa. In the same data set, HSF2, which has not previously been linked to cancer, displayed decreased expression. Using 3-dimensional (3D) organotypic PrCa cultures that spontaneously undergo an invasive conversion, opposite effects of HSF1 and HSF2 were observed; tumor spheroids lacking HSF1 grew slowly, were polarized and devoid of invasive structures, and depletion of HSF2 potentiated invasiveness. In the in vivo xenograft chorioallantoic membrane model, HSF1 silencing caused tumor regression and fibrosis, and knockdown of HSF2 generated large invasive tumors, verifying the results from the 3D-cultures. Gene expression profiling revealed enrichment of genes connected to translational control when either HSF1 or HSF2 was silenced. HSF1-specific targets were associated with progression of tumorigenesis, whereas HSF2 targets were involved in focal adhesion, critical for invasion. This study provides the first evidence for HSF2 functioning in cancer, i.e. as a tumor suppressor. Moreover, human PrCa tissue microarrays demonstrated increased nuclear HSF1 expression, which significantly correlated with high-grade Gleason score. Cytoplasmic HSF1 was detected in a subset of tumors and intriguingly, correlated with decreased disease-specific survival. This was most pronounced in intermediate Gleason score 7 tumors and in metastases. We propose the use of HSF1 as a biomarker to predict PrCa outcome, thus facilitating clinical decision-making and supporting individualized treatment choices. HSF1 and HSF2 siRNA transfection was performed in triplicates (biological replicates), for 5 and 8 days prior to harvesting total RNA; and compared to PC-3 cells transfected with scrambled control siRNAs for 5 and 8 days, respectively.
2013-12-23 | E-GEOD-48672 | biostudies-arrayexpress
Project description:Heat shock transcription factors HSF1 and HSF2 both are necessary for proper spermatogenesis, which is disrupted at elevated temperatures. We studied how HSF1 and HSF2 cooperate during the heat shock response in mouse spermatocytes. For this purpose we used ChIP-sequencing. ChIP-Seq analyses revealed that the temperature elevation induces remodeling of HSF1 and HSF2 binding to chromatin. The highest HSF1-chromatin binding was observed at 43°C, when HSF2-chromatin binding was reduced. Many promoters (mainly Hsp genes) were occupied by both heat shock factors at physiological temperature of testes and/or at 38°C. In contrary at 43°C only HSF1 was bound. Obtained results suggest that HSF1 and HSF2 could cooperate in regulation of the transcription of some genes only at physiological temperatures and/or at 38°C. Alteration in HSFs interactions and their binding to chromatin could be one of the reason of increased spermatogenic cell death observed after heat shock.
2014-10-07 | GSE56735 | GEO
Project description:Prompt and accurate responses to DNA damage are crucial for maintaining normal cellular homeostasis and avoiding cell death. These responses involve the activation of DNA repair pathways and changes in gene expression. RNA polymerase II (RNAPII) is responsible for transcribing protein-coding genes and small nuclear RNAs (snRNAs). Concurrent with transcription, pre-mRNA undergoes splicing by the spliceosome, a complex consisting of five ribonucleoproteins (snRNPs), snRNAs, and additional factors, which ensures proper pre-mRNA splicing and generation of mature mRNA, thereby promoting proteome diversity. In this study, we provide new insights into the role of HSF2 in pre-mRNA splicing and maintenance of genomic stability. We observed a significant reduction in RNAPIICTD pS7 following loss of HSF2 and this is accompanied by the inhibition of RNAPII recruitment to snRNA gene promoters and a significant reduction in snRNA transcription. Moreover, the observed reduction in snRNAs expression in cells lacking HSF2 is associated with impaired pre-mRNA splicing and several other consequences. These include a spontaneous increase in DNA damage, enhanced formation of R-loops, and elevated cellular sensitivity to ionizing radiation (IR). These findings suggest that loss of HSF2 leads to multiple disruptions in cellular processes, ultimately resulting in compromised genome stability and increased susceptibility to DNA damage. Furthermore, HSF2-deficient mice exhibit an accelerated IR-induced T cell acute lymphoblastic leukemia (T-ALL), as evidenced by the reduced snRNA levels and expression of IR-induced DNA repair genes. Our findings reveal a previously unrecognized role for HSF2 in the process of snRNA transcription and its loss highlights its pathological consequences. These features are also mirrored by the loss of the HSF2 target gene, HSP110, suggesting that HSP110 contributes, at least in part, to the phenotypes observed following HSF2 loss.
2023-08-22 | GSE241102 | GEO
Project description:Heat shock transcription factors HSF1 and HSF2 both are necessary for proper spermatogenesis, which is disrupted at elevated temperatures. We studied how HSF1 and HSF2 cooperate during the heat shock response in mouse spermatocytes. For this purpose we used ChIP-sequencing. ChIP-Seq analyses revealed that the temperature elevation induces remodeling of HSF1 and HSF2 binding to chromatin. The highest HSF1-chromatin binding was observed at 43M-BM-0C, when HSF2-chromatin binding was reduced. Many promoters (mainly Hsp genes) were occupied by both heat shock factors at physiological temperature of testes and/or at 38M-BM-0C. In contrary at 43M-BM-0C only HSF1 was bound. Obtained results suggest that HSF1 and HSF2 could cooperate in regulation of the transcription of some genes only at physiological temperatures and/or at 38M-BM-0C. Alteration in HSFs interactions and their binding to chromatin could be one of the reason of increased spermatogenic cell death observed after heat shock. On Illumina platform we sequenced DNA immunoprecipitated from isolated spermatocytes using anti-HSF1 antibody or anti-HSF2 antibody. Cells were either untreated (control) or heat shocked for 5-20 minutes. Two PCR-verified ChIP replicates were collected per each sample, and three negative control samples with normal goat serum were included.
2014-10-07 | E-GEOD-56735 | biostudies-arrayexpress
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
Project description:Mapping of in vivo targets for HSF2 by using mammalian tissue material in a global ChIP-chip promoter screen. Chromatin was isolated from three wild-type (WT) mouse testes, crosslinked and sonicated into fragments of 100-500 bp, and the quality of the DNA was controlled before the immunoprecipitation, showing no signs of degradation. The DNA amplified from the HSF2 immunoprecipitation samples was labeled and hybridized against the total input DNA samples, on a 1.5 kb promoter tiling array (NimbleGen Systems Inc.), covering ~26000 promoters of the mouse genome. After hybridization and scanning, HSF2 hybridization signals were Lowess normalized to produce log2 ratios (HSF2 ChIP/Input DNA) for all replicate arrays. The promoter values were calculated as average log2 ratios over all probes for each promoter. To identify the HSF2 target population, we used a non-arbitrary analysis method called RankProd described in Breitling et al. 2004. RankProd has been published as an R/Bioconductor package. Keywords: 1.5 kb mouse promoter ChIP-chip (MM5, NimbleGen Systems Inc.), mouse testis
2008-08-06 | GSE9289 | GEO
Project description:Mapping of in vivo targets for HSF2 by using mammalian tissue material in a global ChIP-chip promoter screen. Chromatin was isolated from three wild-type (WT) mouse testes, crosslinked and sonicated into fragments of 100-500 bp, and the quality of the DNA was controlled before the immunoprecipitation, showing no signs of degradation. The DNA amplified from the HSF2 immunoprecipitation samples was labeled and hybridized against the total input DNA samples, on a 1.5 kb promoter tiling array (NimbleGen Systems Inc.), covering ~26000 promoters of the mouse genome. After hybridization and scanning, HSF2 hybridization signals were Lowess normalized to produce log2 ratios (HSF2 ChIP/Input DNA) for all replicate arrays. The promoter values were calculated as average log2 ratios over all probes for each promoter. To identify the HSF2 target population, we used a non-arbitrary analysis method called RankProd described in Breitling et al. 2004. RankProd has been published as an R/Bioconductor package. Keywords: 1.5 kb mouse promoter ChIP-chip (MM5, NimbleGen Systems Inc.), mouse testis HSF2 ChIP sample vs. Input sample (reference), biological replicates: 3, one replicate per array.
2008-08-05 | E-GEOD-9289 | biostudies-arrayexpress
Project description:YAP controls cell migration and invasion through a Rho-GTPase switch
| PRJNA1223913 | ENA