We have defined a distinct genome-wide transcriptional program that HSF1 coordinates in malignancy. This program includes some heat-shock proteins well known to be involved in oncogenic programs, such as Hsp90 (Whitesell and Lindquist, 2005
). However, it differs fundamentally from the HSF1 program induced by thermal stress, in that it includes many genes that are not induced by heat shock and does not include many that typically are. This cancer program is commonly activated in a wide variety of human malignancies. It is strongly associated with metastasis and death in at least the three cancers responsible for ~30% of all cancer-related deaths worldwide: those of the breast, colon and lung. The very broad range of tumors in which we see immunohistochemical evidence of HSF1 activation suggests it will play a pervasive role throughout tumor biology.
What types of cellular processes does HSF1 regulate in cancer? They constitute an astonishingly diverse group that extends far beyond protein folding, and includes energy metabolism, cell cycle signalling, DNA repair, apoptosis, cell adhsion, extracellular matrix formation, and translation. Some of these processes were previously known to be affected by HSF1 (Dai et al., 2007
; Jin et al., 2011
; Zhao et al., 2009
). However, the common assumption had been that HSF1s affects were mediated primarily by Hsp chaperone activities (Jin et al., 2011
; Meng et al., 2010
; Solimini et al., 2007
). The remarkable breadth of the HSF1 cancer program in humans explains why HSF1 is such a powerful modifier of tumorigenesis in multiple animal models (Dai et al., 2007
; Jin et al., 2011
; Zhao et al., 2009
) and why HSF1 was identified as one of only six potent metastasis-promoting genes in a genome-wide screen for enhancers of invasion by malignant melanoma cells (Scott et al., 2011
Not only is the repertoire of HSF1-regulated genes in cancer much larger than just heat-shock genes, but even the manner in which some of the classical heat-shock genes are regulated differs. For example, HSPA6 (HSP70B’), a pillar of the heat-shock response, differs dramatically in these two states. Following heat stress, HSPA6 is the most highly induced of all mRNAs, yet, surprisingly in cancer, HSPA6 is only bound very weakly by HSF1. Its expression is not changed following HSF1 depletion and its transcript level does not correlate with that of HSF1 in our meta-analysis of 12,000 gene expression experiments.
What could account for activation of a distinct HSF1-regulated program in cancer? After many years of investigation, we do not yet fully understand how HSF1 activity is regulated during the classic heat-shock response. Multiple mechanisms have been described. These include the release of HSF1 from its normal sequestration by chaperones when unfolded substrates compete for chaperone binding. But in addition, HSF1 is subject to extensive array of post-translational modifications (at least 30) including acetylation, sumoylation and numerous phosphorylations (Anckar and Sistonen, 2011
Some of these heat-shock regulatory mechanisms are likely shared by cancer cells. For instance, impaired protein homeostasis driven by the accumulation of mutant, misfolding-prone oncoproteins, aneuploidy and the increased rate of translation in cancer could chronically stimulate HSF1 activation by releasing it from sequestration from chaperones (Anckar and Sistonen, 2011
). Dysregulation of signaling pathways in cancer could also drive post-translational modifications to HSF1. Some of these (such as those responsible for phosphorylation at serine 326) will likely be shared with heat-shocked cells. But others will likely be unique to cancer. Indeed, it seems extremely likely that different mechanisms of activiation will operate in different cancers. Several pathways activated in cancer such as EGFR/HER2 axis (Zhao et al., 2009
), the RAS/MAPK (Stanhill et al., 2006
) or the insulin/IGFI-like growth factor system (Chiang et al., 2012
) have all been reported to alter HSF1 activity. Additional modes of cancer-specific regulation might include epigenetic states common to cancer and proliferating cells and transcriptional co-regulators.
How might the distinct transcriptional program regulated by HSF1 in malignancy have arisen? The association of this program with metastasis and death points to an evolutionary origin distinct from cancer itself. The broad range of cancer types in which we find HSF1 activated suggests that this program originated to support basic biological processes. Indeed, the sole heat-shock factor in yeast (yHSF), even at basal temperatures, binds many genes that are involved in a wide-range of core cellular functions (Hahn et al., 2004
). These transcriptional targets allow yeast not only to adapt to environmental co ntingencies but also to modulate metabolism and maintain proliferation under normal growth conditions (Hahn et al., 2004
; Hahn and Thiele, 2004
). As a result, yHSF is essential for viability, paralleling the importance of HSF1 for the survival and proliferation of cancer cells (Dai et al., 2007
). Activation of HSF1 may also be required in animals in states of high proliferation and altered metabolism such as immune activation and wound healing (Rokavec et al., 2012
; Xiao et al., 1999
; Zhou et al., 2008
). Moreover, in diverse eukaryotes, HSF is a well-validated longevity factor; non-classical activation of this transcription factor could be highly relevant in this context (Chiang et al., 2012
; Volovik et al., 2012
Ironically, the evolutionarily ancient role played by HSF1 in helping cells to adapt, survive and proliferate is co-opted frequently to support highly malignant cancers. By enabling oncogenesis, the activation of this ancient pro-survival mechanism thereby actually impairs survival of the host. HSF1 activation in a particular tumor may reflect the degree to which accumulated oncogenic mutations have disrupted normal physiology even before overt invasion or metastasis occurs. This interpretation would explain the impressively broad prognostic value of our HSF1-cancer signature across disparate cancers and even at early stages of disease. Clinical implementation will require further refinement of the signature and validation in tissue and RNA samples from multiple clinical cohorts. Such studies are certainly warranted. As just one potential application, it might aid in the identification of indolent tumors that do not require intervention, reducing the burdens of unnecessary treatment (Kalager et al., 2012
). In addition to its prognostic value, HSF1 and diverse regulators that activate it might prove useful targets for cancer therapeutics.
Our understanding of the extensive role played by HSF1 in supporting cancers continues to mature. The protein has been defined for decades by its ability to coordinate chaperone protein expression and enhance survival in the face of heat stress (Christians et al., 2002
; Ritossa, 1962
). While appreciating the importance of these classical mechanisms, the role of HSF1 is clearly much broader and deeper.