HSF1Base: A Comprehensive Database of HSF1 (Heat Shock Factor 1) Target Genes

Kovács, Dániel; Sigmond, Tímea; Hotzi, Bernadette; Bohár, Balázs; Fazekas, Dávid; Deák, Veronika; Vellai, Tibor; Barna, János

doi:10.3390/ijms20225815

Cited by 68 publications

(62 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HSP90 and HSP70 act as cellular repressor of HSF1 and play a major role in retaining HSF1 in a monomeric state. Induction of transcriptional activity by cellular stress then results in the conversion of HSF1 from an inactive monomer to a DNA-binding trimer [29, 30]. Despite its central role in stress resistance, disease and aging, the mechanisms controlling HSF1 transactivation remain incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

Cuevas-Mora

Roque

Sales

et al. 2020

Preprint

View full text Add to dashboard Cite

Loss of proteostasis and cellular senescence are key hallmarks of aging. Recent studies suggest that lung fibroblasts from idiopathic pulmonary fibrosis (IPF) show features of cellular senescence, decline in heat shock proteins (HSPs) expression and impaired protein homeostasis (proteostasis). However, direct cause-effect relationships are still mostly unknown. In this study, we sought to investigate whether the heat shock factor 1 (HSF1), a major transcription factor that regulates the cellular HSPs network and cytoplasmic proteostasis, contributes to cellular senescence in lung fibroblasts. We found that IPF lung fibroblasts showed an upregulation in the expression of various cellular senescence markers, including β -galactosidase activity (SA-β-gal) staining, the DNA damage marker γ H2Ax, the cell cycle inhibitor protein p21, and multiple senescence-associated secretory proteins (SASP), as well as upregulation of collagen 1a1, fibronectin and alpha-smooth muscle actin (α-SMA) gene expression compared with age-matched controls. These changes were associated with impaired proteostasis, as judged by an increase in levels of p-HSF1 ser307 and HSF1 K298 sumo , downregulation of HSPs expression, and increased cellular protein aggregation. Similarly, lung fibroblasts isolated from a mouse model of bleomycin-induced lung fibrosis and mouse lung fibroblast chronically treated with H 2 O 2 showed downregulation in HSPs and increased in cellular senescence and SASP markers. Moreover, sustained pharmacologic activation of HSF1 increased the expression of HSPs, reduced cellular senescence markers and effectively reduced the expression of pro-fibrotic genes in IPF fibroblast. Our data provide evidence that the HSF1-mediated proteostasis is important for driving lung fibroblasts toward cellular senescence and a myofibroblast phenotype. We postulate that enhancing HSF1 activity could be effective in the treatment of lung fibrosis. METHODSAnimals. C57B/6J mice (8-10 weeks old) were purchased from the Jackson Laboratory (Bar Harbor, ME) and housed in a pathogen-free animal facility at Thomas Jefferson University. Throughout the study period, mice were maintained on a standard chow diet (13.5% calories from fat, 58% from carbohydrates, and 28.5% from protein) and permitted to feed ad libitum. ). They were isolated from the uninvolved periphery of the organ of six lung cancer patients. Fresh tissues were transported immediately to the laboratory for isolating fibroblasts according to procedures described before [35].Bleomycin-induced lung injury: Bleomycin sulphate (Enzo life science, BML-AP302-0050) was dissolved in phosphate buffered saline. Lung injury was induced by instilling 0.04U of bleomycin into the posterior oropharynx of anesthetized mice every other week for five doses [36]. The mice were observed following intubation to ensure complete recovery from anesthesia. Mice were euthanized 2 weeks after the last dose by exposure to carbon dioxide, and lungs were harvested for fibroblast isolation and histological preparation...

show abstract

Section: Introductionmentioning

confidence: 99%

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

Cuevas-Mora

Roque

Sales

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…7l, m). Notably, the genes encoding for FN1, SERPINH1, and MMP9 were previously shown to be direct transcriptional targets of HSF1 20,[37][38][39] . Taken together these findings suggest that inflammation induces the activation of HSF1 in stromal fibroblasts, leading to ECM remodeling through activation of ECM proteins, such as FN1, matrix remodeling enzymes such as MMP7 and MMP9, supporting chaperones such as the collagen chaperone SER-PINH1, and immune regulatory proteins such as LCN2 and S100A8.…”

Section: Loss Of Hsf1 Attenuates Inflammation-induced Colon Cancermentioning

confidence: 99%

Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer

et al. 2020

View full text Add to dashboard Cite

In the colon, long-term exposure to chronic inflammation drives colitis-associated colon cancer (CAC) in patients with inflammatory bowel disease. While the causal and clinical links are well established, molecular understanding of how chronic inflammation leads to the development of colon cancer is lacking. Here we deconstruct the evolving microenvironment of CAC by measuring proteomic changes and extracellular matrix (ECM) organization over time in a mouse model of CAC. We detect early changes in ECM structure and composition, and report a crucial role for the transcriptional regulator heat shock factor 1 (HSF1) in orchestrating these events. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell-culture, prevents inflammation-induced ECM remodeling in mice and inhibits progression to CAC. Establishing relevance to human disease, we find high activation of stromal HSF1 in CAC patients, and detect the HSF1-dependent proteomic ECM signature in human colorectal cancer. Thus, HSF1-dependent ECM remodeling plays a crucial role in mediating inflammation-driven colon cancer.

show abstract

“…The mechanisms through which HSF1 affects biological activities in the HSR are therefore proposed to be primarily through transcriptional regulation and recruitment of transcriptional and DNA modifying proteins, and extends to the downstream activities performed by the protein products of its target genes ( Figure 1). The extent of HSF1 DNA-binding sites and genes subject to HSF1 regulation were shown by several genomic, microarray, and/or transcriptomic studies [39][40][41], the targets of which have recently been collated [42].…”

Section: Introductionmentioning

confidence: 99%

HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity

Prince

Lang

Guerrero-Gimenez

et al. 2020

Cells

View full text Add to dashboard Cite

Heat shock factor 1 (HSF1) is the primary component for initiation of the powerful heat shock response (HSR) in eukaryotes. The HSR is an evolutionarily conserved mechanism for responding to proteotoxic stress and involves the rapid expression of heat shock protein (HSP) molecular chaperones that promote cell viability by facilitating proteostasis. HSF1 activity is amplified in many tumor contexts in a manner that resembles a chronic state of stress, characterized by high levels of HSP gene expression as well as HSF1-mediated non-HSP gene regulation. HSF1 and its gene targets are essential for tumorigenesis across several experimental tumor models, and facilitate metastatic and resistant properties within cancer cells. Recent studies have suggested the significant potential of HSF1 as a therapeutic target and have motivated research efforts to understand the mechanisms of HSF1 regulation and develop methods for pharmacological intervention. We review what is currently known regarding the contribution of HSF1 activity to cancer pathology, its regulation and expression across human cancers, and strategies to target HSF1 for cancer therapy.

show abstract

HSF1Base: A Comprehensive Database of HSF1 (Heat Shock Factor 1) Target Genes

Cited by 68 publications

References 87 publications

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer

HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity

Contact Info

Product

Resources

About