Molecular Mechanisms of Heat Shock Factors in Cancer

Abstract

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.

Keywords: carcinogenesis; heat shock factor; heat shock response; proteotoxic stress; transcription.

Figure 1

Domain organization of human heat shock transcription factors (HSFs). Schematic illustration of human HSF1 (hHSF1), HSF2 (hHSF2), and HSF4 (hHSF4) with the known functional domains. The number indicates the last amino acid of each protein. Each HSF contains a winged helix–turn–helix DNA-binding domain and an oligomerization domain (HR-A/B). The HR-C domain in HSF1 and HSF2 suppresses HSF oligomerization and keeps them inactive under normal conditions. HSFs modulate transcription via the activatory domain, and in HSF1 the regulatory domain controls stress responsiveness. HSF1 and HSF2 display ~39% identical amino acid sequence, whereas HSF1 and HSF4 display ~42% similarity. Note that the figure is not drawn to scale.

Figure 2

Breast cancer cells use HSFs to drive various tumor-promoting mechanisms. Several mechanisms contribute to the activation of human HSFs in breast cancer. Upon activation, trimeric HSF1, HSF2 and HSF4 bind to DNA and initiate the transcription of their target genes, which are involved in tumorigenesis. Multiple proteins enhance the activation of HSF1 by regulating its phosphorylation status. The hormone 17β-estradiol (E2) binds to and activates estrogen receptor alpha (ERα), which leads to HSF1 phosphorylation through the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) pathway, in which the kinases MEK and ERK increase the phosphorylation of HSF1, most probably in the cytoplasm. Activation of HSF1 is also enhanced by epidermal growth factor receptor 2 (HER2), which increases the phosphorylation of HSF1 by the intermediate kinases phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT). Phosphorylated residues in HSF1 that are known to repress the trans-activating capacity of HSF1, are dephosphorylated (Pi) by a complex consisting of the transcription factor immeadiate early response gene 5 protein (IER5) and protein phosphatase 2 (PP2A), thereby promoting HSF1 activation. In the nucleus, once activated, HSF1 induces the transcription of genes encoding heat shock proteins (HSPs), which enhance migration, proliferation, and oncogenic maturation as well as decrease cell–cell adhesion. HSF2 and the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1) cooperatively induce the transcription of pri-mir-183/96/182, and following post-transcriptional processing, these miRNA molecules stimulate migration and proliferation. For example, mir-183, targets the small GTPase RAB21, a protein that prevents aneuploidy. HSF2 also stimulates the expression of Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase (ALG3), an enzyme involved in modulating migration and proliferation in breast cancer cells. HSF2 together with HSF4 modulates the transcription of hypoxia-inducible factor 1 alpha (HIF-1α), a transcription factor regulating a myriad of genes, including vascular endothelial growth factor (VEGF) that promotes angiogenesis. Abbreviation: P, phosphorylation.

Figure 3

Hepatocellular carcinoma (HCC) cells use HSFs to promote metabolic reprograming and cancer invasion. In HCC, trimeric human HSF1, HSF2 and HSF4 bind to DNA and induce the transcription of genes that modulate multiple biological processes that support tumorigenesis. HSF1 enhances the expression of miR-135b that targets reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and ecotropic viral integration site 5 protein homolog (EVI5), both of which are repressors of migration and invasion. Together, HSF2 and euchromatic histone lysine methyl transferase 2 (EHMT2) promote methylation of the gene encoding fructose-bisphosphatase 1 (FBP1), resulting in a decreased expression of FBP1, an enzyme that can counteract glycolysis and inhibit the expression of hypoxia-inducible factor 1 alpha (HIF-1α). Together with HSF4, HSF2 modulates the expression of HIF-1α, which regulates a myriad of genes, including glucose transporter GLUT1, hexokinase-2 (HK2), and l-lactate dehydrogenase A (LDHA), all of which are involved in various steps of the glycolysis pathway in HCC. HIF-1α can also facilitate the activation of protein kinase B (AKT), which promotes epithelial-mesenchymal transition (EMT). Abbreviations: Me1/Me2, mono/di-methylation; P, phosphorylation; TCA, tricarboxylic acid cycle.