Proteomic instability is causally related to human diseases. In guarding proteome stability, the heat shock factor 1 (HSF1)-mediated proteotoxic stress response plays a pivotal role. Contrasting with its beneficial role of enhancing cell survival, recent findings have revealed a compelling pro-oncogenic role for HSF1. However, the mechanisms underlying the persistent activation and function of HSF1 within malignancy remain poorly understood. Emerging evidence reveals that oncogenic signaling mobilizes HSF1 and that cancer cells rely on HSF1 to avert proteomic instability and repress tumor-suppressive amyloidogenesis. In aggregate, these new developments suggest that cancer cells endure chronic proteotoxic stress and that proteomic instability is intrinsically associated with malignant state, a characteristic that could be exploited to combat cancer.

Intrinsic stress response pathways are frequently mobilized within tumor cells. The mediators of these adaptive mechanisms and how they contribute to carcinogenesis remain poorly understood. A striking example is heat shock factor 1 (HSF1), master transcriptional regulator of the heat shock response. Surprisingly, we found that loss of the tumor suppressor gene neurofibromatosis type 1 (Nf1) increased HSF1 levels and triggered its activation in mouse embryonic fibroblasts. As a consequence, Nf1 -/-cells acquired tolerance to proteotoxic stress. This activation of HSF1 depended on dysregulated MAPK signaling. HSF1, in turn, supported MAPK signaling. In mice, Hsf1 deficiency impeded NF1-associated carcinogenesis by attenuating oncogenic RAS/MAPK signaling. In cell lines from human malignant peripheral nerve sheath tumors (MPNSTs) driven by NF1 loss, HSF1 was overexpressed and activated, which was required for tumor cell viability. In surgical resections of human MPNSTs, HSF1 was overexpressed, translocated to the nucleus, and phosphorylated. These findings reveal a surprising biological consequence of NF1 deficiency: activation of HSF1 and ensuing addiction to this master regulator of the heat shock response. The loss of NF1 function engages an evolutionarily conserved cellular survival mechanism that ultimately impairs survival of the whole organism by facilitating carcinogenesis. IntroductionEvolutionarily conserved from yeasts to humans, the heat shock transcription factor heat shock factor 1 (HSF1) is activated by a broad range of stressors that extend far beyond heat, including heavy metals, UV radiation, hypoxia, desiccation, and acidosis (1). During activation, HSF1 undergoes phosphorylation and other posttranslational modifications, trimerization, and nuclear translocation. This results in rapid, high-affinity binding of HSF1 to consensus heat shock elements (HSEs) within the promoters of target genes (2). Such binding drives the induction or suppression of hundreds of genes in mammalian cells (3).The adaptive response unleashed by HSF1 activation is critical for maintaining homeostasis of the cell's proteome, mediated in large part by increased expression of classical heat shock proteins such as HSP27, HSP70, and HSP90 (4). However, the effect of HSF1 activation goes far beyond these chaperones. It helps coordinate a range of fundamental cellular processes that are important to the fitness of malignant cells, including cell cycle control, ribosome biogenesis, protein translation, and glucose metabolism (5, 6). As a result, HSF1 both facilitates initial oncogenic transformation and maintains the malignant phenotype of established cancer cell lines driven by a wide range of mutations. In mice and in cell culture, genetic ablation of Hsf1 expression potently impairs tumorigenesis and cellular transformation driven by oncogene activation or tumor suppressor loss (5). The importance of HSF1 in enabling malignancy has been demonstrated by other recent work as well

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Beyond protein synthesis and autophagy, emerging evidence has implicated mTORC1 in regulating protein folding and proteasomal degradation as well, highlighting its prominent role in cellular proteome homeostasis or proteostasis. In addition to growth signals, mTORC1 senses and responds to a wide array of stresses, including energetic/metabolic stress, genotoxic stress, oxidative stress, osmotic stress, ER stress, proteotoxic stress, and psychological stress. Whereas growth signals unanimously stimulate mTORC1, stresses exert complex impacts on mTORC1, most of which are repressive. mTORC1 suppression, as a generic adaptive strategy, empowers cell survival under various stressful conditions. In this essay, we provide an overview of the emerging role of mTORC1 in proteostasis, the distinct molecular mechanisms through which mTORC1 reacts to diverse stresses, and the schemes exploited by cancer cells to circumvent stress-induced mTORC1 suppression. Hence, acting as a stress sensor, mTORC1 intimately couples stresses to cellular proteostasis.