Heat shock factor 1 (HSF1)-targeted anticancer therapeutics: overview of current preclinical progress

ABSTRACT

Introduction: The heat shock factor 1 (HSF1) plays a pivotal role in guarding proteome stability or proteostasis by induction of heat shock proteins (HSPs). While HSF1 remains mostly latent in unstressed normal cells, it is constitutively active in malignant cells, rendering them addicted to HSF1 for their growth and survival. HSF1 affects tumorigenesis, cancer progression, and treatment resistance by preserving cancer proteostasis, thus suggesting disruption of HSF1 activity as a potential anticancer strategy.

Areas covered: In this review, we focus on the HSF1 activation cycle and its interaction with HSPs, the role of HSF1 in oncogenesis, and development of HSF1-targeted drugs as a potential anticancer therapy for disrupting cancer proteostasis.

Expert opinion: HSF1 systematically maintains proteostasis in malignant cancer cells. Although genomic instability is widely accepted as a hallmark of cancer, little is known about the role of proteostasis in cancer. Unveiling the complicated mechanism of HSF1 regulation, particularly in cancer cells, will enable further development of proteostasis-targeted anticancer therapy.

Abbreviations: AMPK: AMP-activated protein kinase; DBD: DNA-binding domain; HR-A/B; HR-C: heptad repeats; HSE: heat shock elements; HSF1: heat shock factor; HSPs: heat shock proteins; HSR: heat shock response; MEK: mitogen-activated protein kinase kinase; mTOR: mammalian target of rapamycin; NF1: neurofibromatosis type 1; P-TEFb: positive transcription elongation factor b; RD: regulatory domain; RNAi: RNA interference; TAD: transactivation domain; TRiC: TCP-1 ring complex

KEYWORDS:

• Heat shock factor 1
• heat shock proteins
• proteostasis
• cancer
• targeted therapy

Article highlights

• Heat shock factor 1 (HSF1) is an evolutionarily conserved transcription factor that initiates the cytoprotective heat shock response (HSR), which induces the expression of large amounts of heat shock proteins (HSPs) to reestablish homeostasis of the cellular proteome, or proteostasis.

• Malignant cells suffer chronic proteotoxic stress. Proteotoxic microenvironments promote a higher demand for HSPs to maintain mutated or overexpressed oncogenes, thus rendering malignant cells to become addicted to HSF1 activity. The remarkable difference in HSF1 dependency between normal and malignant cells makes HSF1 exploitable for anti-cancer therapy.

• The HSF1 activation cycle includes trimerization, nuclear translocation, DNA binding, post-translational modification, and transcription of HSPs. The interaction between HSF1 and HSPs, particularly HSP90 and HSP70, is thought to modulate HSF1 transcriptional activity, though the finer details of this complex process are still being identified.

• Disrupting cancer proteostasis by targeting its master transcriptional regulator represents a novel anticancer therapeutic strategy. Various small molecules inhibiting HSF1-mediated induction of HSPs are known to possess anticancer activity, although many of these agents lack specificity for HSF1.

• Targeting HSF1 may also prove useful in combination therapies to mitigate the counterproductive activation of HSF1 triggered by proteasome inhibitors and HSP90 inhibitors.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded