HSF1 Activation Mechanisms, Disease Roles, and Small Molecule Therapeutics

Abstract

The heat shock factor 1 (HSF1) is a master transcription regulator that orchestrates the expression of heat shock proteins (HSPs) in response to various cellular stresses. Dysfunction of HSF1 contributes to the pathogenesis of a spectrum of acute and chronic diseases, including cancer. Consequently, the modulation of HSF1 activity through the development of small molecules emerges as a promising therapeutic strategy for disease treatment. The activation of HSF1 is a multifaceted process, governed by a complex interplay of regulatory mechanisms, including post-translational modifications, protein-protein interactions, and a balance between its activation and inactivation. Recently, a plethora of compounds, ranging from synthetic to naturally derived, that either inhibit or activate HSF1 was identified, holding considerable potential for the treatment of numerous human diseases. In this comprehensive review, we elucidate the sophisticated mechanisms underlying activation of human HSF1, introduce its role in the etiology of diseases, and provide a comprehensive summary of the inhibitors and activators of HSF1 that have been discovered to date. This review not only offers novel insights for the development of small molecule therapeutics targeting HSF1 but also charts new territories in the design of innovative interventions for the amelioration of disease.

Keywords: HSF1; activators; cancer; inhibitors; therapeutic strategy.

Figure 1

The activation mechanism of HSF1. (A) Upper panel: An architectural blueprint of the HSF1 protein. It consists of a DNA-binding domain (DBD), a heptad repeat region (HR) that exhibits leucine-zipper-like characteristics, a regulatory domain (RD), and a trans-activation domain (TAD). Lower panel: Under stress, the quiescent HSF1, which is normally sequestered within a complex with HSPs and the chaperonin TRiC, is released. This liberation triggers a conformational change, leading to the formation of active HSF1 trimers that migrate to the nucleus. (B) The HSF1 trimers subsequently bind to the HSE sequences, thereby initiating the transcription of HSPs. Throughout this transcriptional cascade, the activity of HSF1 is finely tuned by an array of PTMs such as phosphorylation, dephosphorylation, acetylation, and sumoylation, along with interactions from various proteins that can either enhance or repress its activity. (C) The activity of active HSF1 is gradually attenuated through inhibitory acetylation and sumoylation. Additionally, the binding of HSP70 to HSF1 acts as a crucial feedback loop that inhibits HSF1 activity and leads to the cessation of HSP transcription. (D) Following attenuation, HSF1 is released from the DNA and undergoes deactivation. It can either revert to monomeric form, associate with inhibitory protein complexes, or be targeted for ubiquitination and degradation. Figure was created in BioRender.

Figure 2

The expression and prognostic value of HSF1 in pan-cancer. (A) Radar chart represents the expression of HSF1 in various cancer types. Notably, HSF1 is highly expressed in BLCA, BRCA, CHOL, COAD, ESCA, GBM, HNSC, KICH, KIRC, KIRP, LIHC, LUAD, LUSC, PRAD, READ, STAD and THCA. (B) The HSF1 interactome was generated through GeneMania database analysis, integrating experimental evidence and bioinformatic predictions to produce an unbiased protein-protein interaction (PPI) network. This network offers valuable insights into the interactive partners of HSF1. (C) The prognostic potential of HSF1 in pan-cancer. (D) Kaplan-Meier overall survival (OS) curves are presented to compare the survival rates between patients with high and low HSF1 expression. The elevated HSF1 expression is associated with a poorer prognosis in patients with ACC, BLCA, LIHC, LUSC, SARC, and UCS.

Figure 3

HSF1 plays a pivotal role in the progression of numerous diseases, highlighting its complex and multifaceted involvement in cellular processes. (A) In the context of cancer, HSF1 promotes the initiation and progression of the disease by enhancing protein biosynthesis. This increased biosynthetic activity is particularly advantageous for cancer cells, as it supports their rapid growth and proliferation. By upregulating the transcription of genes encoding ribosomal proteins and other factors involved in protein synthesis, HSF1 contributes to the creation of a favorable microenvironment for tumor development. (B) Misfolded protein aggregates lead to the occurrence of neurodegenerative diseases, and the expression of HSPs mediated by HSF1 can exert protective effects by mitigating cellular stress and promoting cell survival, which prevent the progress of this diseases. (C) Beyond cancer and neurodegenerative diseases, HSF1 has also been implicated in a wide range of other human diseases. For instance, it has been shown to play a role in obesity, where it may contribute to metabolic dysregulation and the development of insulin resistance. In myocardial injury, HSF1 activation is linked to the protection of cardiomyocytes from stress-induced damage, suggesting a potential therapeutic target for heart disease. Similarly, in acute lung and brain injury, HSF1-mediated HSPs expression may provide cytoprotective effects, although the precise mechanisms involved remain under investigation. Additionally, HSF1 regulates the expression of genes involved in endometriosis, suggesting a potential role in the disease's pathogenesis. HSF1 is a key player in the progression of multiple diseases, with its effects ranging from promotional to protective depending on the specific context. Figure was created in BioRender.