HSF1 as a Cancer Biomarker and Therapeutic Target

Abstract

Heat shock factor 1 (HSF1) was discovered in 1984 as the master regulator of the heat shock response. In this classical role, HSF1 is activated following cellular stresses such as heat shock that ultimately lead to HSF1-mediated expression of heat shock proteins to protect the proteome and survive these acute stresses. However, it is now becoming clear that HSF1 also plays a significant role in several diseases, perhaps none more prominent than cancer. HSF1 appears to have a pleiotropic role in cancer by supporting multiple facets of malignancy including migration, invasion, proliferation, and cancer cell metabolism among others. Because of these functions, and others, of HSF1, it has been investigated as a biomarker for patient outcomes in multiple cancer types. HSF1 expression alone was predictive for patient outcomes in multiple cancer types but in other instances, markers for HSF1 activity were more predictive. Clearly, further work is needed to tease out which markers are most representative of the tumor promoting effects of HSF1. Additionally, there have been several attempts at developing small molecule inhibitors to reduce HSF1 activity. All of these HSF1 inhibitors are still in preclinical models but have shown varying levels of efficacy at suppressing tumor growth. The growth of research related to HSF1 in cancer has been enormous over the last decade with many new functions of HSF1 discovered along the way. In order for these discoveries to reach clinical impact, further development of HSF1 as a biomarker or therapeutic target needs to be continued.

Keywords: EMT; HSF1; biomarker; invasion; metastasis; migration; therapy..

Fig. (1).

Heat Shock Factor 1 (HSF1) Gene. A) There are six human HSF isoforms all containing a homologous DNA binding domain recognizing the heat shock element (HSE). B) HSF1 is located on the long arm of chromosome 8 at q24.3. The resulting gene has 13 exons with a full gene size of 23,135 bp that transcribes to an mRNA of 2,193 bp. The resulting protein is 529 aa and has multiple functional domains. The DNA binding domain (DBD) is a winged helix-turn-helix domain. The leucine zipper (LZ) domains mediate the trimerization of HSF1 upon activation. The regulatory domain is home to many post-translational modifications that appear to regulate HSF1 transcriptional activity with Ser326 seemingly the key phosphorylation necessary for activity. The transactivation domain (TAD) of HSF1 recruits p-TEFb to release proximal promoter pausing and promote transcription elongation of target genes.

Fig. (2).

HSF1 Function in Tumorigenesis and Tumor Progression. HSF1 has been shown to be phosphorylated and activated at Ser326 by AKT1 [61], MEK [69], p38 [123], and mTOR [124]. HSF1 directly regulates multiple genes to promote migration, invasion, and EMT that ultimately translates to tumor progression and metastasis. HSF1 also appears to directly upregulate and downregulate several genes that lead to enhanced cell proliferation and survival. In addition, HSF1 has direct effects on genes that promote the Warburg effect of increasing glycolysis in cancer cells. Together these functions, and others, suggest HSF1 has multiple effects that lead to tumorigenesis and tumor progression.