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.
Highlights
The heat shock response is one of the most explosive biochemical events experienced in mammalian cells [1]
While higher levels of Heat shock factor 1 (HSF1) expression do positively correlate with HSF1 gene targets in human breast tumor samples (Figure 3), and HSF1 overexpression in cultured cancer cells can lead to increased heat shock protein (HSP) levels [61,66], HSF1 activation appears to be primarily regulated at the protein level as may be expected when an immediate transcriptional response is required, such as when the heat shock response (HSR) is deployed [67]
Most normal and malignant cells respond to mitogenic growth factors (GFs), and HSF1 appears to be required for downstream signaling from a range of GFs, including the heregulin receptor Her3 (ERBB3), the ligandless Her2 receptor, and the platelet-derived growth factor receptor (PDGFR) [45,60,63,64]
Summary
The heat shock response is one of the most explosive biochemical events experienced in mammalian cells [1]. The first indication that HSF1 might be constitutively active in human tumors was that its gene targets, HSPs, such as Hsp and Hsp, almost exclusively silent in normal tissues, were avidly expressed in breast cancer and other malignancies [8,57,58]. While higher levels of HSF1 expression do positively correlate with HSF1 gene targets in human breast tumor samples (Figure 3), and HSF1 overexpression in cultured cancer cells can lead to increased HSP levels [61,66], HSF1 activation appears to be primarily regulated at the protein level as may be expected when an immediate transcriptional response is required, such as when the HSR is deployed [67]. HSF1 mRNA expression, protein levels, and promoter occupancy across the different HSP genes in human breast cancer. The mRNA expression levels were obtained from The Cancer Genome Atlas [73], downloaded from the NIH Genomic Data Commons portal (https://portal.gdc.cancer.gov/). (B) Example scatterplot of the relationship between HSF1 mRNA expression and HSP90AB1 mRNA expression
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