The Multifaceted Role of HSF1 in Tumorigenesis

Abstract

Heat Shock Factor 1 (HSF1), the master transcriptional regulator of the heat shock response (HSR), was first cloned more than 30 years ago. Most early research interrogating the role that HSF1 plays in biology focused on its cytoprotective functions, as a factor that promotes the survival of organisms by protecting against the proteotoxicity associated with neurodegeneration and other pathological conditions. However, recent studies have revealed a deleterious role of HSF1, as a factor that is co-opted by cancer cells to promote their own survival to the detriment of the organism. In cancer, HSF1 operates in a multifaceted manner to promote oncogenic transformation, proliferation, metastatic dissemination, and anti-cancer drug resistance. Here we review our current understanding of HSF1 activation and function in malignant progression and discuss the potential for HSF1 inhibition as a novel anticancer strategy. Collectively, this ever-growing body of work points to a prominent role of HSF1 in nearly every aspect of carcinogenesis.

Keywords: Cancer; Chaperones; Gene regulatory networks; HSF1; Heat shock; Heat shock proteins; Stress response; Transcription factor; Tumor.

Figure 1.. HSF1 activation by multiple mechanisms in cancer.

1) Chaperone Sequestration: Under basal conditions, HSF1 remains suppressed by heat shock proteins such as HSP70. In response to proteotoxic stress or increased levels of protein synthesis, HSF1 is titrated away from HSP70. Subsequently, HSF1 is phosphorylated, trimerizes and translocates to the nucleus. In the nucleus, HSF1 binds to HSEs of target genes and induces gene expression. 2) Oncogenic Signaling: Oncogenic signaling pathways activated by either oncogene activation or tumor suppressor loss can regulate HSF1 activity. HER2 drives PI3K/AKT signaling, which in turn promotes the phosphorylation and inactivation of GSK3β. GSK3β phosphorylates HSF1 on S303/307 to inhibit its activity. Activating mutations in RAS activate downstream effectors that include MEK, which interacts with and phosphorylates HSF1 on S326 leading to its activation. Loss of the tumor suppressor neurofibromatosis type 1 (NF1) can also activate RAS leading to increased levels of HSF1 phosphorylation, trimerization, nuclear localization, and transcriptional activation. Loss of tumor suppressor kinase LKB1 inhibits AMPK, which normally inhibits HSF1 via S121 phosphorylation. 3) DNA copy number: An increase in HSF1 gene copy number can increase HSF1 mRNA and protein levels. 4) mRNA expression levels: NOTCH1 binds directly to the promoter of the HSF1 gene leading to an increase in HSF1 mRNA and protein levels. 5) Protein stability: The F-box/WD repeat-containing protein 7 (FBXW7) is an E3 ubiquitin ligase that targets HSF1 for ubiquitylation and proteasomal degradation. Loss of FBXW7 in many cancers leads to an increase in HSF1 stability.

Figure 2.. Schematic of HSF1 targets and their role in malignancy.

HSF1 promotes carcinogenesis by activating the canonical heat shock proteins (HSPs) and non-canonical genes. HSF1 activates canonical HSPs such as HSP70 and HSP90. HSPs contribute to cancer programs by different mechanisms. HSP70 inhibits apoptosis; while HSP90 drives heterogeneity, which in turn can leads to tumor transformation and drug resistance. DNAJB8 can differentiate non-cancer stem cells into cancer-stem cells (CSC) by inducing expression of SOX2. HSF1 also promotes tumorigenesis by enhancing transcription of genes that encode non-HSP factors. HSF1 promotes the expression of HuR, which is involved in translation and/or mRNA stability. HSF1 also activates the expression of adhesion proteins such as vinculin, which promotes cell adhesion and spreading.