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Review
. 2016 Jan;26(1):17-28.
doi: 10.1016/j.tcb.2015.10.011. Epub 2015 Nov 18.

HSF1: Guardian of Proteostasis in Cancer

Chengkai Dai  1 , Stephen Byers Sampson  2
Affiliations
Review

HSF1: Guardian of Proteostasis in Cancer

Chengkai Dai et al. Trends Cell Biol. 2016 Jan.

Abstract

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 the malignant state, a characteristic that could be exploited to combat cancer.

Keywords: HSF1; amyloidogenesis; proteome homeostasis; proteotoxic stress; tumor suppression.

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Figures

Figure 1
Figure 1. Multi-step activation of HSF1 by stress
Under non-stressed conditions, inactive monomeric HSF1 remains repressed by the products of its own transcriptional targets, HSPs, in the cytoplasm. Proteotoxic stressors, such as heat shock, trigger dissociation of the repressive protein complex and release of monomeric HSF1. Subsequently, HSF1 undergoes trimerization, nuclear translocation, and posttranslational modifications including phosphorylation, acetylation, and sumoylation. Among these modifications, phosphorylation is well documented and has been shown to critically regulate HSF1 activation. In the nucleus, activated trimeric HSF1, with the assistance of the single-stranded DNA-binding protein RPA, the chromatin-remodeling enzyme BRG1, and the histone chaperone FACT, accesses and binds to HSEs, which subsequently trigger recruitment of a pre-initiation complex that comprises RNA polymerase II (RNA Pol II) and general transcription factors (TFII). Abbreviations: HDAC6, histone deacetylase 6; RPA, replication protein A; BRG1, brahma related gene 1; FACT, facilitates chromatin transcription. E1, 2, n: HSP gene exons.
Figure 2
Figure 2. Oncogenic and tumor-suppressive signaling intimately regulates HSF1
(A) In healthy cells, mitogenic RAS signaling activates HSF1 through MEK-mediated Ser326 phosphorylation. ERK, the canonical substrate for MEK, suppresses MEK-mediated HSF1 activation through inhibitory Thr292/386 phosphorylation of MEK, in a negative feedback manner. Congruent with its role as a negative regulator of RAS, the tumor suppressor NF1 inactivates HSF1. In addition, tumor-suppressive LKB1 signaling could inactivate HSF1 through AMPK-mediated Ser121 phosphorylation. AMPK, a pivotal sensor of energy depletion, critically regulates the MSR. Through mobilization of AMPK, metabolic stressors, including metformin and nutrient deprivation, inactivate HSF1. Abbreviations: S, serine; T, threonine; Y, tyrosine. (B) Germline mutations in the NF1 and LKB1 gene cause Neurofibromatosis type I and Peutz-Jeghers Syndrome, respectively, in humans. Afflicted humans are predisposed to cancer. While in NF1-deficient cells hyper-activated oncogenic RAS signaling causes constitutive Ser326 phosphorylation and activation of HSF1, in LKB1-deficient cells hypo-activation of AMPK leads to impaired HSF1 Ser121 phosphorylation, a modification inhibitory to HSF1 activation.
Figure 3
Figure 3. HSF1 guards cancer proteomic stability and enables effective stress adaptation
(A) Cancer cells with constitutive HSF1 activation possess abundant chaperoning capacity, thereby averting proteomic instability. Moreover, HSF1 regulates numerous non-HSP genes that are engaged in diverse cellular processes, thereby orchestrating a preemptive systemic response that empowers cells to promptly adapt to stress. (B) Impairment of HSF1 activation depletes cellular chaperoning capacity, inevitably provoking protein destabilization and misfolding. Accumulated misfolded proteins further form either amorphous aggregates or, ultimately, amyloids. In addition, the stress-adapting ability of cancer cells is severely compromised. As a consequence, robust malignant phenotypes can no longer be sustained. m7G: mRNA 7-methylguanosine cap; AAAAA: mRNA poly(A) tail; HSP: heat-shock protein; HSF1: heat shock factor 1; Ub: ubiquitin.
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