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

Abstract

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.

Augmentation of the heat shock axis during exceptional longevity in Ames dwarf mice

“…The role of HSF1 in exceptional longevity, usual aging, and the proteostasis network mostly is documented in lower, poikilothermic organisms such as C. elegans [8][9][10]. HSF1 is subject to feedback inhibition through interaction with heat shock proteins (HSPs), HBP1, and by direct acetylation [11][12][13][14]. Deacetylase activity of sirtuin 1 protein (SIRT1) and other deacetylases facilitate HSF1 binding to a DNA sequence consisting of inverted repeats of nGAAn known as heat shock element (HSE) [15][16][17].…”

The functions and regulation of heat shock proteins; key orchestrators of proteostasis and the heat shock response

“…However, a definitive hypothesis for the mechanism of coordination between the trimerization, DNA binding and regulatory domain has not been coherently developed. This difficulty may reflect the structural flexibility of much of the HSF1 sequence outside of the DNA-binding and trimerization domains, which has led to uncertainties in defining three-dimensional structures and critical residues in HSF1 mediated transcription for many regions of the protein, reviewed in (Prince et al 2020).…”

Small Heat Shock Proteins in Cancers: Functions and Therapeutic Potential for Cancer Therapy

“…Some (HspB1, HspB5, HspB6, HspB8) are ubiquitously expressed in various tissues, while others are expressed in specific tissues (Table 1). In eukaryotes, the expression of sHSPs is under the control of the heat shock factor (HSF) transcription factors, which can initiate transcription of sHSPs genes and upregulate the expression of sHSPs in response to stress [13,14]. Moreover, sHSPs themselves are sensitive to their conditions, and their expression of proteins is coordinated by cellular conditions [15].…”

“…Importantly, it should be noted that HspB1 involvement in modulating CSC properties depends on the levels of its expression and activity. Though HspB1 can be expressed constitutively in mammalian cells, its expression is mainly coordinated by HSF1 (heat shock transcription factor 1), which is a stress-responsive transcriptional factor that induces the transcriptional activation and the expression of HSPs such as HspB1 and Hsp70 [13]. Under any proteotoxic stress (heat, hypoxia, energy starvation) stimuli, HSF1 is activated and translocated into the nucleus, where it activates HSP gene transcription.…”