3297

HSF1

Heat shock transcription factor 1 (HSF1) is the master regulator of the heat shock response. Accumulating evidence shows that HSF1 is overexpressed in a variety of human cancers, is associated with cancer aggressiveness, and could serve as an independent diagnostic or prognostic biomarker. In this review, we will provide an overview of the multifaceted roles of HSF1 in cancer, with a special focus on the four underlying molecular mechanisms involved. First, HSF1 regulates the expression of heat shock proteins (HSPs) including HSP90, HSP70, and HSP27. Second, HSF1 regulates cellular metabolism, including glycolysis and lipid metabolism. Third, HSF1 serves as a regulator of different signaling pathways, such as HuR-HIF-1, Slug, protein kinase C (PKC), nuclear factor-kappaB (NF-kappaB), PI3K-AKT-mTOR, and mitogen-activated protein kinase (MAPK) pathways. Finally, HSF1 regulates microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Overall, HSF1 plays many important roles in cancer via regulating cell proliferation, anti-apoptosis, epithelial-mesenchymal transition (EMT), migration, invasion, and metastasis and may be a potential therapeutic target for human cancers.

OBJECTIVE: Reprogramming energy metabolism has been defined as the ninth hallmark of cancer; glucose deprivation might be a novel, feasible and effective approach for cancer treatment. However, the comprehensive illustration of behavior alteration of hepatocellular carcinoma (HCC) cells induced by glucose restriction is lacking and associated molecular mechanism is still unclear. METHODS: Three human HCC cell lines were cultured with normal control (25.0 mM D-glucose) and low glucose (5.5 mM D-glucose) Dulbecco's modified Eagle's medium. Cell migration ability was assessed by both transwell migration assay and wound healing assay. Levels of heat shock factor 1 (HSF1) and epithelial-mesenchymal transition (EMT) markers, E-cadherin and N-cadherin, were estimated by real-time polymerase chain reaction and western blotting. Moreover, low glucose-induced inhibition of EMT-associated migration via the HSF1 was demonstrated in HCC cells by knocking down HSF1 with the HSF1 siRNA technique; in terms of molecular mechanism, direct regulation of HSF1 on snail1 expression was identified by chromatin immunoprecipitation followed by Luciferase reporter assay. RESULTS: Herein, we showed that low glucose culture hampered typical EMT-like morphological change, "cadherin switching," and cell migration of HCC cells and further demonstrated that persistent down-regulation of HSF1 induced by glucose restriction, resulting in direct inhibition of snail1 expression and promoting the up-regulation of E-cadherin expression, and HSF1 was required for EMT-associated migration of HCC cells when cultured with low glucose media. CONCLUSION: All these results illustrate that glucose restriction can repress the EMT and migration of HCC cells, and demonstrate the importance of HSF1 to our understanding on HCC treatment as a novel and effective therapeutic target or adjuvant strategy.

Ovarian cancer is the most lethal gynecological cancer, with over 200,000 women diagnosed each year and over half of those cases leading to death. The proteotoxic stress-responsive transcription factor HSF1 is frequently overexpressed in a variety of cancers and is vital to cellular proliferation and invasion in some cancers. Upon analysis of various patient data sets, we find that HSF1 is frequently overexpressed in ovarian tumor samples. In order to determine the role of HSF1 in ovarian cancer, inducible HSF1 knockdown cell lines were created. Knockdown of HSF1 in SKOV3 and HEY ovarian cancer cell lines attenuates the epithelial-to-mesenchymal transition (EMT) in cells treated with TGFbeta, as determined by western blot and quantitative RT-PCR analysis of multiple EMT markers. To further explore the role of HSF1 in ovarian cancer EMT, we cultured multicellular spheroids in a non-adherent environment to simulate early avascular tumors. In the spheroid model, cells more readily undergo EMT; however, EMT inhibition by HSF1 becomes more pronounced in the spheroid model. These findings suggest that HSF1 is important in the ovarian cancer TGFbeta response and in EMT.

Heat shock factor 1 (HSF1) is highly expressed in various malignancies and is a potential modulator of tumor progression. Emerging evidence suggests that HSF1 activation in stromal cells is closely related to poor patient prognosis. However, the role of HSF1 in oral squamous cell carcinoma (OSCC) remains elusive. We aimed to investigate the function of HSF1 in cancer-associated fibroblasts (CAFs) of the tumor microenvironment (TME) and in tumor development. In the present study, we found that HSF1 was highly expressed in both CAFs and tumor cells, and was significantly correlated with poor prognosis and overall survival. Moreover, HSF1 overexpression in CAFs resulted in a fibroblast-like phenotype of Cal27 cells, induced epithelial-mesenchymal transition (EMT), and promoted proliferation, migration and invasion in Cal27 cells. HSF1 knockdown attenuated features of CAFs and reduced EMT, proliferation, migration and invasion in Cal27 cells. Furthermore, HSF1 in CAFs promoted tumor growth in nude mice. Taken together, these data suggest that HSF1 expression in CAFs drive OSCC progression, and could serve as an independent prognostic marker of patients with OSCC. Thus, HSF1 is a potent mediator of OSCC malignancy.CI - (c) 2019 The Authors. cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese cancer Association.

Heat shock transcription factor 1 (HSF1), the major regulator of stress response, is frequently activated in cancer and has an apparent role in malignant transformation. Here we analyzed the influence of the over-expression of a constitutively active transcriptionally-competent HSF1 mutant form on phenotypes of mouse and human melanoma cells. We observed that the expression of active HSF1 supported anchorage-independent growth in vitro, and metastatic spread in the animal model in vivo, although the proliferation rate of cancer cells was not affected. Furthermore, active HSF1 enhanced cell motility, reduced the adherence of cells to a fibronectin-coated surface, and affected the actin cytoskeleton. We found that although the expression of active HSF1 did not affect levels of epithelial-to-mesenchymal transition markers, it caused transcriptional down-regulation of vinculin, protein involved in cell motility, and adherence. Functional HSF1-binding sites were found in mouse and human Vcl/VCL genes, indicating a direct role of HSF1 in the regulation of this gene. An apparent association between HSF1-induced down-regulation of vinculin, increased motility, and a reduced adherence of cells suggests a possible mechanism of HSF1-mediated enhancement of the metastatic potential of cancer cells.CI - Copyright (c) 2014. Published by Elsevier Inc.