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Key Points Heat shock factors (HSFs) are essential for all organisms to survive exposures to stress, as they bind heat shock elements to induce transcription of heat shock proteins (HSPs). In addition, the HSFs are important regulators involved in development, lifespan and disease, thereby integrating pathways of stress responses and normal physiology. The mammalian HSF family consists of four members: HSF1, HSF2, HSF3 and HSF4. Distinct HSFs possess unique and overlapping functions, with a great variation in expression patterns, post-translational modifications (PTMs) and interacting protein partners. HSFs are composed of functional domains, of which the DNA-binding domain is best preserved. The HSF1 activation–attenuation cycle involves trimerization, strict regulation by multiple PTMs, such as acetylation, phosphorylation and sumoylation, and feedback from HSPs. Functional crosstalk between HSF family members facilitates the fine-tuning of HSF-mediated gene regulation. HSF-knockout mouse models have made it possible to identify many targets, which have further extended the impact of HSFs in developmental processes, such as oogenesis, corticogenesis and spermatogenesis. The ability to sense and respond to environmental challenges is important for lifespan, and HSF1 is a longevity factor that prevents global instability of the proteome during ageing. The life-promoting function of HSF1 is strictly controlled by the insulin and insulin-like signalling pathway in Caenorhabditis elegans . HSF1 is a potent modifier of tumorigenesis and HSF1 deficiency in mice counteracts tumour initiation and progression. HSF1 is therefore a potential cancer drug target. As many human, age-related pathologies are associated with stress and misfolded proteins, several small-molecule activators and inhibitors of HSFs could be used for pharmacologic modulation of HSF-mediated gene regulation. Heat shock factors (HSFs) are essential for survival in a stressful environment. HSFs mediate the heat shock response by binding heat shock elements present in heat shock protein (HSP) genes, thereby mediating their transcription. They are also important regulators of development, lifespan and disease. Heat shock factors (HSFs) are essential for all organisms to survive exposures to acute stress. They are best known as inducible transcriptional regulators of genes encoding molecular chaperones and other stress proteins. Four members of the HSF family are also important for normal development and lifespan-enhancing pathways, and the repertoire of HSF targets has thus expanded well beyond the heat shock genes. These unexpected observations have uncovered complex layers of post-translational regulation of HSFs that integrate the metabolic state of the cell with stress biology, and in doing so control fundamental aspects of the health of the proteome and ageing.

Malignant transformation is accompanied by alterations in the key cellular pathways that regulate development, metabolism, proliferation and motility as well as stress resilience. The members of the transcription factor family, called heat shock factors (HSFs), have been shown to play important roles in all of these biological processes, and in the past decade it has become evident that their activities are rewired during tumorigenesis. This review focuses on the expression patterns and functions of HSF1, HSF2, and HSF4 in specific cancer types, highlighting the mechanisms by which the regulatory functions of these transcription factors are modulated. Recently developed therapeutic approaches that target HSFs are also discussed.

Programs of gene expression are executed by a battery of transcription factors that coordinate divergent transcription from a pair of tightly linked core initiation regions of promoters and enhancers. Here, to investigate how divergent transcription is reprogrammed upon stress, we measured nascent RNA synthesis at nucleotide-resolution, and profiled histone H4 acetylation in human cells. Our results globally show that the release of promoter-proximal paused RNA polymerase into elongation functions as a critical switch at which a gene’s response to stress is determined. Highly transcribed and highly inducible genes display strong transcriptional directionality and selective assembly of general transcription factors on the core sense promoter. Heat-induced transcription at enhancers, instead, correlates with prior binding of cell-type, sequence-specific transcription factors. Activated Heat Shock Factor 1 (HSF1) binds to transcription-primed promoters and enhancers, and CTCF-occupied, non-transcribed chromatin. These results reveal chromatin architectural features that orient transcription at divergent regulatory elements and prime transcriptional responses genome-wide. Heat Shock Factor 1 (HSF1) is a regulator of stress-induced transcription. Here, the authors investigate changes to transcription and chromatin organization upon stress and find that activated HSF1 binds to transcription-primed promoters and enhancers, and to CTCF occupied, untranscribed chromatin.

Wnt-11 promotes cancer cell migration and invasion independently of β-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD 8 is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-β signals to promote EMT. FZD8 mRNA is upregulated in multiple prostate cancer datasets and in metastatic cancer cell lines in vitro and in vivo. Analysis of patient samples reveals increased levels of FZD 8 in cancer, correlating with Wnt-11. FZD 8 co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt-11 activation of ATF2-dependent transcription. FZD8 silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-β/Smad-dependent signaling. Mechanistically, FZD 8 forms a TGF-β-regulated complex with TGF-β receptors that is mediated by the extracellular domains of FZD 8 and TGFBR1. Targeting FZD 8 may therefore inhibit aberrant activation of both Wnt and TGF-β signals in prostate cancer. Wnt11 has been shown to play a role in invasion and metastasis of prostate cancer. Here the authors show that in prostate cancer cells Wnt11 signals through the Fzd8 receptor and report an interaction between Fzd8 and TGF-β receptors regulating the transcription of a subset of TGF-beta genes.

The Human gamma-herpesviruses Kaposi’s sarcoma herpesvirus (KSHV) and Epstein-Barr virus (EBV) are causally associated to a wide range of cancers. While the default infection program for these viruses is latent, sporadic lytic reactivation supports virus dissemination and oncogenesis. Despite its relevance, the repertoire of host factors governing the transition from latent to lytic phase is not yet complete, leaving much of this complex process unresolved. Here we show that heat shock factor 2 (HSF2), a transcription factor involved in regulation of stress responses and specific cell differentiation processes, promotes gamma-herpesvirus lytic gene expression. In lymphatic endothelial cells infected with KSHV and in gastric cancer cells positive for EBV, ectopic HSF2 enhances the expression of lytic genes; While knocking down HSF2 significantly decreases their expression. HSF2 overexpression is accompanied by decreased levels of repressive histone marks at the promoters of the lytic regulators KSHV ORF50 and EBV BZLF1, both characterized by poised chromatin features. Our results demonstrate that endogenous HSF2 binds to the promoters of KSHV ORF50 and EBV BZLF1 genes and shifts the bivalent chromatin state towards a more transcriptionally permissive state. We detected HSF2 binding to the ORF50 promoter in latent cells, in contrast, in lytic cells, HSF2 occupancy at the ORF50 promoter is lost in conjunction with its proteasomal degradation. These findings identify HSF2 as a regulator of gamma-herpesvirus lytic gene expression in latency and offer new insights on the function of this transcription factors at poised gene promoters, improving our understanding of its role in differentiation and development.

Heat shock factor 1 (HSF1) is essential for protecting cells from protein-damaging stress associated with misfolded proteins and regulates the insulin-signaling pathway and aging. Here, we show that human HSF1 is inducibly acetylated at a critical residue that negatively regulates DNA binding activity. Activation of the deacetylase and longevity factor SIRT1 prolonged HSF1 binding to the heat shock promoter Hsp70 by maintaining HSF1 in a deacetylated, DNA-binding competent state. Conversely, down-regulation of SIRT1 accelerated the attenuation of the heat shock response (HSR) and release of HSF1 from its cognate promoter elements. These results provide a mechanistic basis for the requirement of HSF1 in the regulation of life span and establish a role for SIRT1 in protein homeostasis and the HSR.

Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. We have used this mutationally fixed conformation to map HSP90 binding sites on HSF1. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response.

Heat shock factors (HSFs) are the master regulators of transcription under protein-damaging conditions, acting in an environment where the overall transcription is silenced. We determined the genomewide transcriptional program that is rapidly provoked by HSF1 and HSF2 under acute stress in human cells. Our results revealed the molecular mechanisms that maintain cellular homeostasis, including HSF1-driven induction of polyubiquitin genes, as well as HSF1- and HSF2-mediated expression patterns of cochaperones, transcriptional regulators, and signaling molecules. We characterized the genomewide transcriptional response to stress also in mitotic cells where the chromatin is tightly compacted. We found a radically limited binding and transactivating capacity of HSF1, leaving mitotic cells highly susceptible to proteotoxicity. In contrast, HSF2 occupied hundreds of loci in the mitotic cells and localized to the condensed chromatin also in meiosis. These results highlight the importance of the cell cycle phase in transcriptional responses and identify the specific mechanisms for HSF1 and HSF2 in transcriptional orchestration. Moreover, we propose that HSF2 is an epigenetic regulator directing transcription throughout cell cycle progression.

Crystal structures of human HSF2 DNA-binding domain bound to DNA, along with biochemical and cellular analyses, offer insight into potential regulatory interactions of this transcription factor. Heat-shock transcription factor (HSF) family members function in stress protection and in human diseases including proteopathies, neurodegeneration and cancer. The mechanisms that drive distinct post-translational modifications, cofactor recruitment and target-gene activation for specific HSF paralogs are unknown. We present crystal structures of the human HSF2 DNA-binding domain (DBD) bound to DNA, revealing an unprecedented view of HSFs that provides insights into their unique biology. The HSF2 DBD structures resolve a new C-terminal helix that directs wrapping of the coiled-coil domain around DNA, thereby exposing paralog-specific sequences of the DBD surface for differential post-translational modifications and cofactor interactions. We further demonstrate a direct interaction between HSF1 and HSF2 through their coiled-coil domains. Together, these features provide a new model for HSF structure as the basis for differential and combinatorial regulation, which influences the transcriptional response to cellular stress.

SUMO (small ubiquitin-like modifier) modification regulates many cellular processes, including transcription. Although sumoylation often occurs on specific lysines within the consensus tetrapeptide ΨKxE, other modifications, such as phosphorylation, may regulate the sumoylation of a substrate. We have discovered PDSM (phosphorylation-dependent sumoylation motif), composed of a SUMO consensus site and an adjacent proline-directed phosphorylation site (ΨKxExxSP). The highly conserved motif regulates phosphorylation-dependent sumoylation of multiple substrates, such as heat-shock factors (HSFs), GATA-1, and myocyte enhancer factor 2. In fact, the majority of the PDSM-containing proteins are transcriptional regulators. Within the HSF family, PDSM is conserved between two functionally distinct members, HSF1 and HSF4b, whose transactivation capacities are repressed through the phosphorylation-dependent sumoylation. As the first recurrent sumoylation determinant beyond the consensus tetrapeptide, the PDSM provides a valuable tool in predicting new SUMO substrates.