Acute HSF1 depletion induces cellular senescence through the MDM2-p53-p21 pathway in human diploid fibroblasts

Oda, Tsukasa; Sekimoto, Takayuki; Kurashima, Kiminori; Fujimoto, Mitsuaki; Nakai, Asami; Yamashita, Takayuki

doi:10.1242/jcs.210724

Cited by 27 publications

(31 citation statements)

References 55 publications

(88 reference statements)

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“…HSPs are important in restoring misfolded conformation and prevent excessive protein denaturation and aggregation. HSF1 deficiency has been reported to induce cellular senescence, affecting numerous signaling pathways including redox homeostasis, antioxidant defense and p53 signaling [31, 32]. In this study, we used a targeted approach to examine HSPs levels in the lung fibroblast, measuring only changes in three key HSPs; HSP70, HSP90, and HSP40, known to be expressed in mouse and human respiratory tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Despite its central role in stress resistance, disease and aging, the mechanisms controlling HSF1 transactivation remain incompletely understood. Initially, HSF1 was believed to cause cellular senescence only in situations in which cellular expression is diminished [31, 32]. In this scenario, reduced expression of HSF1 has been shown to cause senescence by eliciting a proteostasis collapse, thereby compromising the ability of cells to perform essential biological activities.…”

Section: Introductionmentioning

confidence: 99%

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

Cuevas-Mora

Roque

Sales

et al. 2020

Preprint

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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...

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Section: Discussionmentioning

confidence: 99%

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

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“…during cancer therapy) is associated with activation of the p53-p21 and p38-NF-κB axes of SASP (senescenceassociated secretory phenotype) and inhibition of HSF1 activity. Moreover, it has been found that HSF1 depletion alone is sufficient to induce senescence in normal fibroblasts [62]. A positive feedback regulation has been observed.…”

Section: Role Of Hsf1 and P53 Signaling In Cell Fate And Agingmentioning

confidence: 97%

Interplay between HSF1 and p53 signaling pathways in cancer initiation and progression: non-oncogene and oncogene addiction

et al. 2019

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Background The p53 and HSF1 transcription factors are key players in cellular responses to stress. They activate important signaling pathways triggering adaptive mechanisms that maintain cellular homeostasis. HSF1 is mainly activated by proteotoxic stress, and its induction leads to the synthesis of chaperones that provide proteome integrity. The p53 protein, which is primarily activated in response to DNA damage, causes cell cycle arrest allowing for DNA repair or directs cells to apoptosis, thereby maintaining genome integrity. Both signaling pathways are also involved in neoplastic transformation and tumor progression. Loss of tumor suppressor abilities of the wild-type p53 protein results in oncogenesis, whereas proper HSF1 action, though nononcogenic itself, actively supports this process. Conclusions Here, we describe in detail the interplay between the p53 and HSF1 signaling pathways, with particular emphasis on the molecular mechanisms involved, as well as their importance for normal cellular behavior, cancer development, the effectiveness of anti-cancer therapies and their toxicity. Detailed knowledge of the complex interplay between HSF1 and p53 may form a basis for the design of new protocols for cancer treatment.

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“…HSF1 actions also intersect with the p53 pathway to determine cell fates, including survival, programmed cell death, or senescence. For example, depletion of HSF1 has been shown to lead to cell senescence and to prevent malignant transformation [64,82]. These studies showed HSF1 depletion led to an increase in p21, which Oda et al demonstrated to be mediated by increased DHS2 expression and p53 stabilization in diploid human fibroblasts and to be independent of altered HSP levels [82].…”

Section: Hsf1 Promotes Evasion Of Cancer Cell Death and Senescencementioning

confidence: 99%

“…For example, depletion of HSF1 has been shown to lead to cell senescence and to prevent malignant transformation [64,82]. These studies showed HSF1 depletion led to an increase in p21, which Oda et al demonstrated to be mediated by increased DHS2 expression and p53 stabilization in diploid human fibroblasts and to be independent of altered HSP levels [82]. HSF1 may also modulate senescence by activating Hsp72 expression, levels that were shown to be key factors in overcoming oncogene-induced senescence [83,84].…”

Section: Hsf1 Promotes Evasion Of Cancer Cell Death and Senescencementioning

confidence: 99%

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

Prince

Lang

Guerrero-Gimenez

et al. 2020

Cells

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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.

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Acute HSF1 depletion induces cellular senescence through the MDM2-p53-p21 pathway in human diploid fibroblasts

Cited by 27 publications

References 55 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

Interplay between HSF1 and p53 signaling pathways in cancer initiation and progression: non-oncogene and oncogene addiction

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

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