Inhibition of HSF1 and SAFB Granule Formation Enhances Apoptosis Induced by Heat Stress.

Stress resistance mechanisms include upregulation of heat shock proteins (HSPs) and formation of granules. Stress-induced granules are classified into stress granules and nuclear stress bodies (nSBs). The present study examined the involvement of nSB formation in thermal resistance. We used chemical compounds that inhibit heat shock transcription factor 1 (HSF1) and scaffold attachment factor B (SAFB) granule formation and determined their effect on granule formation and HSP expression in HeLa cells. We found that formation of HSF1 and SAFB granules was inhibited by 2,5-hexanediol. We also found that suppression of HSF1 and SAFB granule formation enhanced heat stress-induced apoptosis. In addition, the upregulation of HSP27 and HSP70 during heat stress recovery was suppressed by 2,5-hexanediol. Our results suggested that the formation of HSF1 and SAFB granules was likely to be involved in the upregulation of HSP27 and HSP70 during heat stress recovery. Thus, the formation of HSF1 and SAFB granules was involved in thermal resistance.

Generation of GCaMP6s-Expressing Zebrafish to Monitor Spatiotemporal Dynamics of Calcium Signaling Elicited by Heat Stress.

The ability of organisms to quickly sense and transduce signals of environmental stresses is critical for their survival. Ca2+ is a versatile intracellular messenger involved in sensing a wide variety of stresses and regulating the subsequent cellular responses. So far, our understanding for calcium signaling was mostly obtained from ex vivo tissues and cultured cell lines, and the in vivo spatiotemporal dynamics of stress-triggered calcium signaling in a vertebrate remains to be characterized. Here, we describe the generation and characterization of a transgenic zebrafish line with ubiquitous expression of GCaMP6s, a genetically encoded calcium indicator (GECI). We developed a method to investigate the spatiotemporal patterns of Ca2+ events induced by heat stress. Exposure to heat stress elicited immediate and transient calcium signaling in developing zebrafish. Cells extensively distributed in the integument of the head and body trunk were the first batch of responders and different cell populations demonstrated distinct response patterns upon heat stress. Activity of the heat stress-induced calcium signaling peaked at 30 s and swiftly decreased to near the basal level at 120 s after the beginning of exposure. Inhibition of the heat-induced calcium signaling by LaCl3 and capsazepine and treatment with the inhibitors for CaMKII (Ca²2/calmodulin-dependent protein kinase II) and HSF1 (Heat shock factor 1) all significantly depressed the enhanced heat shock response (HSR). Together, we delineated the spatiotemporal dynamics of heat-induced calcium signaling and confirmed functions of the Ca2+-CaMKII-HSF1 pathway in regulating the HSR in zebrafish.

Inhibition of translation initiation factor eIF4a inactivates heat shock factor 1 (HSF1) and exerts anti-leukemia activity in AML.

Eukaryotic initiation factor 4A (eIF4A), the enzymatic core of the eIF4F complex essential for translation initiation, plays a key role in the oncogenic reprogramming of protein synthesis, and thus is a putative therapeutic target in cancer. As important component of its anticancer activity, inhibition of translation initiation can alleviate oncogenic activation of HSF1, a stress-inducible transcription factor that enables cancer cell growth and survival. Here, we show that primary acute myeloid leukemia (AML) cells exhibit the highest transcript levels of eIF4A1 compared to other cancer types. eIF4A inhibition by the potent and specific compound rohinitib (RHT) inactivated HSF1 in these cells, and exerted pronounced in vitro and in vivo anti-leukemia effects against progenitor and leukemia-initiating cells, especially those with FLT3-internal tandem duplication (ITD). In addition to its own anti-leukemic activity, genetic knockdown of HSF1 also sensitized FLT3-mutant AML cells to clinical FLT3 inhibitors, and this synergy was conserved in FLT3 double-mutant cells carrying both ITD and tyrosine kinase domain mutations. Consistently, the combination of RHT and FLT3 inhibitors was highly synergistic in primary FLT3-mutated AML cells. Our results provide a novel therapeutic rationale for co-targeting eIF4A and FLT3 to address the clinical challenge of treating FLT3-mutant AML.

Combined inhibition of AURKA and HSF1 suppresses proliferation and promotes apoptosis in hepatocellular carcinoma by activating endoplasmic reticulum stress.

PURPOSE: In this study we aimed to assess the anti-tumor effect of co-inhibition of Aurora kinase A (AURKA) and heat shock transcription factor 1 (HSF1) on hepatocellular carcinoma (HCC), as well as to explore the mechanism involved. METHODS: Expression of AURKA and HSF1 in primary HCC tissues and cell lines was detected by immunohistochemistry (IHC), qRT-PCR and Western blotting. AURKA was knocked down in HepG2 and BEL-7402 HCC cells using lentivirus-mediated RNA interference. Next, CCK-8, clone formation, transwell and flow cytometry assays were used to assess their viability, migration, invasion and apoptosis, respectively. The expression of proteins related to cell cycle progression, apoptosis and endoplasmic reticulum stress (ERS) was analyzed using Western blotting. In addition, in vivo tumor growth of HCC cells was assessed using a nude mouse xenograft model, and the resulting tumors were evaluated using HE staining and IHC. RESULTS: Both AURKA and HSF1 were highly expressed in HCC tissues and cells, while being negatively related to HCC prognosis. Knockdown of AURKA significantly inhibited the colony forming and migrating capacities of HCC cells. In addition, we found that treatment with an AURKA inhibitor (Danusertib) led to marked reductions in the proliferation and migration capacities of the HCC cells, and promoted their apoptosis. Notably, combined inhibition of AURKA and HSF1 induced HCC cell apoptosis, while increasing the expression of ERS-associated proteins, including p-eIF2α, ATF4 and CHOP. Finally, we found that co-inhibition of AURKA and HSF1 elicited an excellent in vivo antitumor effect in a HCC mouse model with a relatively low cytotoxicity. CONCLUSIONS: Combined inhibition of AURKA and HSF1 shows an excellent anti-tumor effect on HCC cells in vitro and in vivo, which may be mediated by ERS. These findings suggest that both AURKA and HSF1 may serve as targets for HCC treatment.

HSF1 promotes endometriosis development and glycolysis by up-regulating PFKFB3 expression.

BACKGROUND: Endometriosis is a chronic hormonal inflammatory disease characterized by the presence of endometrial tissue outside the uterus. Endometriosis often causes infertility, which brings physical and mental pain to patients and their families. METHODS: We examined the functions of heat shock factor 1 (HSF1) in endometriosis development through cell count assay, cell-scratch assay and clone formation experiments. We used quantitative real-time PCR (qRT-PCR) and Western blot (WB) to detect HSF1 expression. Glucose and lactate levels were determined using a glucose (GO) assay kit and a lactate assay kit. Furthermore, we used a HSF1 inhibitor-KRIBB11 to establish a mouse model of endometriosis. RESULTS: Our data demonstrated that HSF1 promoted endometriosis development. Interestingly, HSF1 enhanced glycolysis via up-regulating PFKFB3 expression in endometriosis cells, which was a key glycolysis enzyme. Consistently, the HSF1 inhibitor KRIBB11 could abrogate endometriosis progression in vivo and in vitro. CONCLUSIONS: Findings indicate that HSF1 plays an important role in endometriosis development, which might become a new target for the treatment of endometriosis. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary data are available.

The proteostasis guardian HSF1 directs the transcription of its paralog and interactor HSF2 during proteasome dysfunction.

Protein homeostasis is essential for life in eukaryotes. Organisms respond to proteotoxic stress by activating heat shock transcription factors (HSFs), which play important roles in cytoprotection, longevity and development. Of six human HSFs, HSF1 acts as a proteostasis guardian regulating stress-induced transcriptional responses, whereas HSF2 has a critical role in development, in particular of brain and reproductive organs. Unlike HSF1, that is a stable protein constitutively expressed, HSF2 is a labile protein and its expression varies in different tissues; however, the mechanisms regulating HSF2 expression remain poorly understood. Herein we demonstrate that the proteasome inhibitor anticancer drug bortezomib (Velcade), at clinically relevant concentrations, triggers de novo HSF2 mRNA transcription in different types of cancers via HSF1 activation. Similar results were obtained with next-generation proteasome inhibitors ixazomib and carfilzomib, indicating that induction of HSF2 expression is a general response to proteasome dysfunction. HSF2-promoter analysis, electrophoretic mobility shift assays, and chromatin immunoprecipitation studies unexpectedly revealed that HSF1 is recruited to a heat shock element located at 1.397 bp upstream from the transcription start site in the HSF2-promoter. More importantly, we found that HSF1 is critical for HSF2 gene transcription during proteasome dysfunction, representing an interesting example of transcription factor involved in controlling the expression of members of the same family. Moreover, bortezomib-induced HSF2 was found to localize in the nucleus, interact with HSF1, and participate in bortezomib-mediated control of cancer cell migration. The results shed light on HSF2-expression regulation, revealing a novel level of HSF1/HSF2 interplay that may lead to advances in pharmacological modulation of these fundamental transcription factors.

Targeting therapy-resistant prostate cancer via a direct inhibitor of the human heat shock transcription factor 1.

Heat shock factor 1 (HSF1) is a cellular stress-protective transcription factor exploited by a wide range of cancers to drive proliferation, survival, invasion, and metastasis. Nuclear HSF1 abundance is a prognostic indicator for cancer severity, therapy resistance, and shortened patient survival. The HSF1 gene was amplified, and nuclear HSF1 abundance was markedly increased in prostate cancers and particularly in neuroendocrine prostate cancer (NEPC), for which there are no available treatment options. Despite genetic validation of HSF1 as a therapeutic target in a range of cancers, a direct and selective small-molecule HSF1 inhibitor has not been validated or developed for use in the clinic. We described the identification of a direct HSF1 inhibitor, Direct Targeted HSF1 InhiBitor (DTHIB), which physically engages HSF1 and selectively stimulates degradation of nuclear HSF1. DTHIB robustly inhibited the HSF1 cancer gene signature and prostate cancer cell proliferation. In addition, it potently attenuated tumor progression in four therapy-resistant prostate cancer animal models, including an NEPC model, where it caused profound tumor regression. This study reports the identification and validation of a direct HSF1 inhibitor and provides a path for the development of a small-molecule HSF1-targeted therapy for prostate cancers and other therapy-resistant cancers.

The Ubiquitin Gene Expression Pattern and Sensitivity to UBB and UBC Knockdown Differentiate Primary 23132/87 and Metastatic MKN45 Gastric Cancer Cells.

Gastric cancer (GC) is one of the most common and lethal cancers. Alterations in the ubiquitin (Ub) system play key roles in the carcinogenetic process and in metastasis development. Overexpression of transcription factors YY1, HSF1 and SP1, known to regulate Ub gene expression, is a predictor of poor prognosis and shorter survival in several cancers. In this study, we compared a primary (23132/87) and a metastatic (MKN45) GC cell line. We found a statistically significant higher expression of three out of four Ub coding genes, UBC, UBB and RPS27A, in MKN45 compared to 23132/87. However, while the total Ub protein content and the distribution of Ub between the conjugated and free pools were similar in these two GC cell lines, the proteasome activity was higher in MKN45. Ub gene expression was not affected upon YY1, HSF1 or SP1 small interfering RNA (siRNA) transfection, in both 23132/87 and MKN45 cell lines. Interestingly, the simultaneous knockdown of UBB and UBC mRNAs reduced the Ub content in both cell lines, but was more critical in the primary GC cell line 23132/87, causing a reduction in cell viability due to apoptosis induction and a decrease in the oncoprotein and metastatization marker ß-catenin levels. Our results identify UBB and UBC as pro-survival genes in primary gastric adenocarcinoma 23132/87 cells.

Neutralization of HSF1 in cells from PIK3CA-related overgrowth spectrum patients blocks abnormal proliferation.

PIK3CA-related overgrowth spectrum is caused by mosaicism mutations in the PIK3CA gene. These mutations, which are also observed in various types of cancer, lead to a constitutive activation of the PI3K/AKT/mTOR pathway, increasing cell proliferation. Heat shock transcription factor 1 (HSF1) is the major stress-responsive transcription factor. Recent findings indicate that AKT phosphorylates and activates HSF1 independently of heat-shock in breast cancer cells. Here, we aimed to investigate the role of HSF1 in PIK3CA-related overgrowth spectrum. We observed a higher rate of proliferation and increased phosphorylation of AKT and p70S6K in mutant fibroblasts than in control cells. We also found elevated phosphorylation and activation of HSF1, which is directly correlated to AKT activation. Specific AKT inhibitors inhibit HSF1 phosphorylation as well as HSF1-dependent gene transcription. Finally, we demonstrated that targeting HSF1 with specific inhibitors reduced the proliferation of mutant cells. As there is currently no curative treatment for PIK3CA-related overgrowth spectrum, our results identify HSF1 as a new potential therapeutic target.

HSF1 inhibition attenuates HIV-1 latency reversal mediated by several candidate LRAs In Vitro and Ex Vivo.

HIV-1 latency is a major barrier to cure. Identification of small molecules that destabilize latency and allow immune clearance of infected cells could lead to treatment-free remission. In vitro models of HIV-1 latency involving cell lines or primary cells have been developed for characterization of HIV-1 latency and high-throughput screening for latency-reversing agents (LRAs). We have shown that the majority of LRAs identified to date are relatively ineffective in cells from infected individuals despite activity in model systems. We show here that, for diverse LRAs, latency reversal observed in model systems involves a heat shock factor 1 (HSF1)-mediated stress pathway. Small-molecule inhibition of HSF1 attenuated HIV-1 latency reversal by histone deactylase inhibitors, protein kinase C agonists, and proteasome inhibitors without interfering with the known mechanism of action of these LRAs. However, latency reversal by second mitochondria-derived activator of caspase (SMAC) mimetics was not affected by inhibition of HSF1. In cells from infected individuals, inhibition of HSF1 attenuated latency reversal by phorbol ester+ionomycin but not by anti-CD3+anti-CD28. HSF1 promotes elongation of HIV-1 RNA by recruiting P-TEFb to the HIV-1 long terminal repeat (LTR), and we show that inhibition of HSF1 attenuates the formation of elongated HIV-1 transcripts. We demonstrate that in vitro models of latency have higher levels of the P-TEFb subunit cyclin T1 than primary cells, which may explain why many LRAs are functional in model systems but relatively ineffective in primary cells. Together, these studies provide insights into why particular LRA combinations are effective in reversing latency in cells from infected individuals.

Reflections and Outlook on Targeting HSP90, HSP70 and HSF1 in Cancer: A Personal Perspective.

This personal perspective focuses on small-molecule inhibitors of proteostasis networks in cancer-specifically the discovery and development of chemical probes and drugs acting on the molecular chaperones HSP90 and HSP70, and on the HSF1 stress pathway. Emphasis is on progress made and lessons learned and a future outlook is provided. Highly potent, selective HSP90 inhibitors have proved invaluable in exploring the role of this molecular chaperone family in biology and disease pathology. Clinical activity was observed, especially in non small cell lung cancer and HER2 positive breast cancer. Optimal use of HSP90 inhibitors in oncology will likely require development of creative combination strategies. HSP70 family members have proved technically harder to drug. However, recent progress has been made towards useful chemical tool compounds and these may signpost future clinical drug candidates. The HSF1 stress pathway is strongly validated as a target for cancer therapy. HSF1 itself is a ligandless transcription factor that is extremely challenging to drug directly. HSF1 pathway inhibitors have been identified mostly by phenotypic screening, including a series of bisamides from which a clinical candidate has been identified for treatment of ovarian cancer, multiple myeloma and potentially other cancers.

Inhibiting Heat Shock Factor 1 in Cancer: A Unique Therapeutic Opportunity.

The ability of cancer cells to cope with stressful conditions is critical for their survival, proliferation, and metastasis. The heat shock transcription factor 1 (HSF1) protects cells from stresses such as chemicals, radiation, and temperature. These properties of HSF1 are exploited by a broad spectrum of cancers, which exhibit high levels of nuclear, active HSF1. Functions for HSF1 in malignancy extend well beyond its central role in protein quality control. While HSF1 has been validated as a powerful target in cancers by genetic knockdown studies, HSF1 inhibitors reported to date have lacked sufficient specificity and potency for clinical evaluation. We review the roles of HSF1 in cancer, its potential as a prognostic indicator for cancer treatment, evaluate current HSF1 inhibitors and provide guidelines for the identification of selective HSF1 inhibitors as chemical probes and for clinical development.

Phosphorylation of HSF1 by PIM2 Induces PD-L1 Expression and Promotes Tumor Growth in Breast Cancer.

Heat shock transcription factor 1 (HSF1) is the master regulator of the proteotoxic stress response, which plays a key role in breast cancer tumorigenesis. However, the mechanisms underlying regulation of HSF1 protein stability are still unclear. Here, we show that HSF1 protein stability is regulated by PIM2-mediated phosphorylation of HSF1 at Thr120, which disrupts the binding of HSF1 to the E3 ubiquitin ligase FBXW7. In addition, HSF1 Thr120 phosphorylation promoted proteostasis and carboplatin-induced autophagy. Interestingly, HSF1 Thr120 phosphorylation induced HSF1 binding to the PD-L1 promoter and enhanced PD-L1 expression. Furthermore, HSF1 Thr120 phosphorylation promoted breast cancer tumorigenesis in vitro and in vivo. PIM2, pThr120-HSF1, and PD-L1 expression positively correlated with each other in breast cancer tissues. Collectively, these findings identify PIM2-mediated HSF1 phosphorylation at Thr120 as an essential mechanism that regulates breast tumor growth and potential therapeutic target for breast cancer. SIGNIFICANCE: These findings identify heat shock transcription factor 1 as a new substrate for PIM2 kinase and establish its role in breast tumor progression.

Inhibition of Heat Shock Factor 1 Enhances Repressive Molecular Mechanisms on the POMC Promoter.

BACKGROUND: Cushing's disease (CD) is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. They express high levels of heat shock protein 90 and heat shock factor 1 (HSF1) in comparison to the normal tissue counterpart, indicating activated cellular stress. AIMS: Our objectives were: (1) to correlate HSF1 expression with clinical features and hormonal/radiological findings of CD, and (2) to investigate the effects of HSF1 inhibition as a target for CD treatment. PATIENTS/METHODS: We examined the expression of total and pSer326HSF1 (marker for its transcriptional activation) by Western blot on eight human CD tumours and compared to the HSF1 status of normal pituitary. We screened a cohort of 45 patients with CD for HSF1 by immunohistochemistry and correlated the HSF1 immunoreactivity score with the available clinical data. We evaluated the effects of HSF1 silencing with RNA interference and the HSF1 inhibitor KRIBB11 in AtT-20 cells and four primary cultures of human corticotroph tumours. RESULTS: We show that HSF1 protein is highly expressed and transcriptionally active in CD tumours in comparison to normal pituitary. The immunoreactivity score for HSF1 did not correlate with the typical clinical features of the disease. HSF1 inhibition reduced proopiomelanocortin (Pomc) transcription in AtT-20 cells. The HSF1 inhibitor KRIBB11 suppressed ACTH synthesis from 75% of human CD tumours in primary cell culture. This inhibitory action on Pomc transcription was mediated by increased glucocorticoid receptor and suppressed Nurr77/Nurr1 and AP-1 transcriptional activities. CONCLUSIONS: These data show that HSF1 regulates POMC transcription. Pharmacological targeting of HSF1 may be a promising treatment option for the control of excess ACTH secretion in CD.

SUMOylation and the HSF1-Regulated Chaperone Network Converge to Promote Proteostasis in Response to Heat Shock.

The role of stress-induced increases in SUMO2/3 conjugation during the heat shock response (HSR) has remained enigmatic. We investigated SUMO signal transduction at the proteomic and functional level during the HSR in cells depleted of proteostasis network components via chronic heat shock factor 1 inhibition. In the recovery phase post heat shock, high SUMO2/3 conjugation was prolonged in cells lacking sufficient chaperones. Similar results were obtained upon inhibiting HSP90, indicating that increased chaperone activity during the HSR is critical for recovery to normal SUMO2/3 levels post-heat shock. Proteasome inhibition likewise prolonged SUMO2/3 conjugation, indicating that stress-induced SUMO2/3 targets are subsequently degraded by the ubiquitin-proteasome system. Functionally, we suggest that SUMOylation can enhance the solubility of target proteins upon heat shock, a phenomenon that we experimentally observed in vitro. Collectively, our results implicate SUMO2/3 as a rapid response factor that coordinates proteome degradation and assists the maintenance of proteostasis upon proteotoxic stress.

HSF1 as a Cancer Biomarker and Therapeutic Target.

Heat shock factor 1 (HSF1) was discovered in 1984 as the master regulator of the heat shock response. In this classical role, HSF1 is activated following cellular stresses such as heat shock that ultimately lead to HSF1-mediated expression of heat shock proteins to protect the proteome and survive these acute stresses. However, it is now becoming clear that HSF1 also plays a significant role in several diseases, perhaps none more prominent than cancer. HSF1 appears to have a pleiotropic role in cancer by supporting multiple facets of malignancy including migration, invasion, proliferation, and cancer cell metabolism among others. Because of these functions, and others, of HSF1, it has been investigated as a biomarker for patient outcomes in multiple cancer types. HSF1 expression alone was predictive for patient outcomes in multiple cancer types but in other instances, markers for HSF1 activity were more predictive. Clearly, further work is needed to tease out which markers are most representative of the tumor promoting effects of HSF1. Additionally, there have been several attempts at developing small molecule inhibitors to reduce HSF1 activity. All of these HSF1 inhibitors are still in preclinical models but have shown varying levels of efficacy at suppressing tumor growth. The growth of research related to HSF1 in cancer has been enormous over the last decade with many new functions of HSF1 discovered along the way. In order for these discoveries to reach clinical impact, further development of HSF1 as a biomarker or therapeutic target needs to be continued.

Small Molecule Inhibitors of HSF1-Activated Pathways as Potential Next-Generation Anticancer Therapeutics.

Targeted therapy is an emerging paradigm in the development of next-generation anticancer drugs. Heat shock factor 1 (HSF1) has been identified as a promising drug target because it regulates several pathways responsible for cancer cell growth, metastasis, and survival. Studies have clearly demonstrated that HSF1 is an effective drug target. Herein, we provide a concise yet comprehensive and integrated overview of progress in developing small molecule inhibitors of HSF1 as next-generation anticancer chemotherapeutics while critically evaluating their potential and challenges. We believe that this review will provide a better understanding of important concepts helpful for outlining the strategy to develop new chemotherapeutic agents with promising anticancer activities by targeting HSF1.

NRF2 and HSF1 coordinately regulate heme oxygenase-1 expression.

Heme oxygenase-1 (HO-1) is an inducible enzyme responding to various stresses and has cytoprotective activities. Although HO-1 has been referred to as heat shock protein (HSP) 32, the heat-mediated induction of HO-1 varies among different species and cell lines. We examined the effects of heat shock on HO-1 expression in mouse embryonic fibroblast (MEF) cells deficient in heat shock factor 1 (HSF1) or nuclear factor-erythroid-2-related factor 2 (NRF2). Heme-induced expression of HO-1 was 2-fold higher in Hsf1-/- cells than in the wild-type cells at both mRNA and protein levels. In Nrf2-/- cells, heme-induced expression of HO-1 was not detected. In contrast, HO-1 expression was markedly induced by heat shock at 40-42 °C in Nrf2-/- cells while the wild-type cells were not responsive. The heat-induced expression of HO-1 in Nrf2-/- cells were almost completely diminished by transfection of siRNA against Hsf1 gene. These results suggest that HSF1 and NRF2 suppress heme-induced and heat-induced HO-1 expression, respectively.

Stress tolerance in diapausing embryos of Artemia franciscana is dependent on heat shock factor 1 (Hsf1).

Embryos of the crustacean, Artemia franciscana, may undergo oviparous development, forming encysted embryos (cysts) that are released from females and enter diapause, a state of suppressed metabolism and greatly enhanced stress tolerance. Diapause-destined embryos of A. franciscana synthesize three small heat shock proteins (sHsps), p26, ArHsp21 and ArHsp22, as well as artemin, a ferritin homologue, all lacking in embryos that develop directly into nauplii. Of these diapause-specific molecular chaperones, p26 and artemin are important contributors to the extraordinary stress tolerance of A. franciscana cysts, but how their synthesis is regulated is unknown. To address this issue, a cDNA for heat shock factor 1 (Hsf1), shown to encode a protein similar to Hsf1 from other organisms, was cloned from A. franciscana. Hsf1 was knocked down by RNA interference (RNAi) in nauplii and cysts of A. franciscana. Nauplii lacking Hsf1 died prematurely upon release from females, showing that this transcription factor is essential to the survival of nauplii. Diapause cysts with diminished amounts of Hsf1 were significantly less stress tolerant than cysts containing normal levels of Hsf1. Moreover, cysts deficient in Hsf1 possessed reduced amounts of p26, ArHsp21, ArHsp22 and artemin, revealing dependence on Hsf1 for expression of their genes and maximum stress tolerance. The results demonstrate an important role for Hsf1, likely in concert with other transcription factors, in the survival and growth of A. franciscana and in the developmentally regulated synthesis of proteins responsible for the stress tolerance of diapausing A. franciscana cysts.

Heat-shock transcription factor 1 is critically involved in the ischaemia-induced cardiac hypertrophy via JAK2/STAT3 pathway.

Cardiac hypertrophy after myocardial infarction (MI) is an independent risk factor for heart failure. Regression of cardiac hypertrophy has emerged as a promising strategy in the treatment of MI patients. Here, we have been suggested that heat-shock transcription factor 1 (HSF1) is a novel repressor of ischaemia-induced cardiac hypertrophy. Ligation of left anterior descending coronary was used to produce MI in HSF1-deficient heterozygote (KO), HSF1 transgenic (TG) mice and their wild-type (WT) littermates, respectively. Neonatal rat cardiomyocytes (NRCMs) were treated by hypoxia to mimic MI in vitro. The HSF1 phosphorylation was significantly reduced in the infarct border zone of mouse left ventricles (LVs) 1 week after MI and in the hypoxia-treated NRCMs. HSF1 KO mice showed more significant maladaptive cardiac hypertrophy and deteriorated cardiac dysfunction 1 week after MI compared to WT MI mice. Deficiency of HSF1 by siRNA transfection notably increased the hypoxia-induced myocardial hypertrophy in NRCMs. Mechanistically, Janus kinase 2 (JAK2) and its effector, signal transducer and activator of transcription 3 (STAT3) were found to be significantly increased in the LV infarct border zone of WT mice after MI as well as the NRCMs treated by hypoxia. These alterations were more significant in HSF1 KO mice and NRCMs transfected with HSF1 SiRNA. Inversely, HSF1 TG mice showed significantly ameliorated cardiac hypertrophy and heart failure 1 week after LAD ligation compared to their WT littermates. Our data collectively demonstrated that HSF1 is critically involved in the pathological cardiac hypertrophy after MI via modulating JAK2/STAT3 signalling and may constitute a potential therapeutic target for MI patients.