Protein homeostasis (proteostasis), or the proper folding and function of the proteome, is vital for cellular and organismal health. Critical to proteostasis is an evolutionarily ancient cytoprotective mechanism originally characterized in cells subjected to elevated temperatures. This mechanism, termed the Heat Shock Response (HSR), is now known to protect against many diverse sources of proteotoxic stress. A hallmark of the HSR is the profound transcriptional induction of molecular chaperones known as heat shock proteins (HSPs), a process regulated by the transcription factor Heat Shock Factor 1 (HSF1). Because this rapid and robust transcriptional induction can be provoked by simply increasing temperature, the HSR has been used as a model system in the gene expression field for decades. As such, the processes that govern HSF1 activation and transcriptional regulation upon heat shock have been extensively studied. However, evidence accumulating over the last decade has revealed a more complicated picture of HSF1 function. We have found that in cancer, HSF1 directly regulates the transcription of genes involved in cellular processes which extend far beyond protein folding, in a manner distinct from the classic HSR. This has been mirrored in studies of HSF1 in other physiological contexts, such as in the tumor microenvironment and in organismal development. The mechanisms which enable HSF1's regulatory plasticity, and the underlying logic that connects the disparate set of HSF1-regulated genes with HSF1's role in proteostasis, is not well understood. Here we propose to use cancer as a as a model system to study the mechanisms that underlie HSF1's non-canonical regulatory roles. Through a series of unbiased proteomic and genetic screens we identify a factor critical for HSF1 in this distinct physiological context, and a surprising multifaceted role for a non-canonical HSF1 target gene in feedback regulation of HSF1 and the HSR. To investigate these mechanisms, we will integrate sophisticated technologies in the field of transcription regulation with established biochemical, genetic and genomic methods. Our studies will provide the knowledge required for the development of therapeutic interventions that promote or inhibit specific programs directed by HSF1. Ultimately, this may enable us to modulate HSF1's non-canonical programs which are implicated in an ever-expanding array of disease states.

The heat shock response (HSR) is a highly conserved adaptive mechanism, regulated by heat shock factors, that acts to help proteins fold and function properly – critical in protecting against neurodegenerative diseases, but also exploited to our detriment to support the anabolic demands of viral infection and cancers. While the mechanistic principles of HSR activation and function have largely been studied in temperature stress, the physiological stresses that are found in normal development and disease are far more complex. This project is focused on elucidating novel mechanisms of heat shock factor function and regulation that are critical for cells coping with growth-related proteotoxic stresses that are relevant to human diseases such as cancer.