The heat-shock, or HSF1-mediated proteotoxic stress, response in cancer: from proteomic stability to oncogenesis

Abstract

The heat-shock, or HSF1-mediated proteotoxic stress, response (HSR/HPSR) is characterized by induction of heat-shock proteins (HSPs). As molecular chaperones, HSPs facilitate the folding, assembly, transportation and degradation of other proteins. In mammals, heat shock factor 1 (HSF1) is the master regulator of this ancient transcriptional programme. Upon proteotoxic insults, the HSR/HPSR is essential to proteome homeostasis, or proteostasis, thereby resisting stress and antagonizing protein misfolding diseases and ageing. Contrasting with these benefits, an unexpected pro-oncogenic role of the HSR/HPSR is unfolding. Whereas HSF1 remains latent in primary cells without stress, it becomes constitutively activated within malignant cells, rendering them addicted to HSF1 for their growth and survival. Highlighting the HSR/HPSR as an integral component of the oncogenic network, several key pathways governing HSF1 activation by environmental stressors are causally implicated in malignancy. Importantly, HSF1 impacts the cancer proteome systemically. By suppressing tumour-suppressive amyloidogenesis, HSF1 preserves cancer proteostasis to support the malignant state, both providing insight into how HSF1 enables tumorigenesis and suggesting disruption of cancer proteostasis as a therapeutic strategy. This review provides an overview of the role of HSF1 in oncogenesis, mechanisms underlying its constitutive activation within cancer cells and its pro-oncogenic action, as well as potential HSF1-targeting strategies.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.

Keywords: HSF1; amyloids; proteostasis; proteotoxic stress; the heat-shock response; tumorigenesis.

Figure 1.

Summary of various post-translational modifications potentially implicated in constitutive activation of HSF1 within cancer cells. Refer to the main text for detailed regulations. Modifications stimulating HSF1 activation are marked in red and modifications inactivating HSF1 are marked in blue. Accordingly, oncoproteins and tumour suppressors are labelled in red and blue, respectively. Proteins displaying both oncogenic and tumour-suppressive roles are labelled in brown. Ac, acetylation; de-phos., de-phosphorylation; K, lysine; polyUb, polyubiquitination; S, serine; T, threonine; Sm, sumoylation.

Figure 2.

Diverse transcription-dependent mechanisms through which HSF1 potently promotes oncogenesis. Through induction of both HSPs and non-HSPs, within cancer cells HSF1 maintains oncogenic signalling, enhances EMT and angiogenesis, promotes genomic instability and preserves proteomic stability. In addition, HSF1 activation within tumour-associated stromal cells can support tumour progression in a non-cell-autonomous fashion.

Figure 3.

HSF1 can exert oncogenic effects via transcription-independent mechanisms. (a) Phosphorylated HSF1 sequesters CDC20 away from APC/C, blocking mitotic exit to promote aneuploidy. (b) Through physical sequestration of JNK apart from mTORC1, HSF1 promotes robust protein synthesis and suppresses autophagy, thereby supporting malignant growth.