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

• Publication year

  2019

• Venue

  Expert opinion on therapeutic targets

• Publication date

  2019-04-07

• Fields of study

  Medicine

• Identifiers
  DOI 10.1080/14728222.2019.1602119PMID 30931649
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The heat-shock, or HSF1-mediated proteotoxic stress, response in cancer: from proteomic stability to oncogenesis

  2018cited by this paper
• Monitoring of the Heat Shock Response with a Real-Time Luciferase Reporter.

  2018cited by this paper
• Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia

  2018cited by this paper
• HSF1 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target

  2018cited by this paper
• Targeting oncogenic Myc as a strategy for cancer treatment

  2018cited by this paper
• Dual targeting of HSP70 does not induce the heat shock response and synergistically reduces cell viability in muscle invasive bladder cancer

  2018cited by this paper
• Increased HSF1 expression predicts shorter disease-specific survival of prostate cancer patients following radical prostatectomy

  2018cited by this paper
• Discovery and optimization of cardenolides inhibiting HSF1 activation in human colon HCT-116 cancer cells

  2018cited by this paper
• Abstract 446: HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation

  2018cited by this paper
• Heat Shock Factor 1 Epigenetically Stimulates Glutaminase-1-Dependent mTOR Activation to Promote Colorectal Carcinogenesis.

  2018cited by this paper
• Induction of Hsp70 in tumor cells treated with inhibitors of the Hsp90 activity: A predictive marker and promising target for radiosensitization

  2017cited by this paper
• Minnelide Inhibits Androgen Dependent, Castration Resistant Prostate Cancer Growth by Decreasing Expression of Androgen Receptor Full Length and Splice Variants

  2017cited by this paper
• New inhibitor targeting human transcription factor HSF1: effects on the heat shock response and tumor cell survival

  2017cited by this paper
• HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation

  2017cited by this paper
• Overexpressed HSF1 cancer signature genes cluster in human chromosome 8q

  2017cited by this paper
• HSF1: Guardian of Proteostasis in Cancer.

  2016cited by this paper
• Structure of human heat-shock transcription factor 1 in complex with DNA

  2016influential reference
• Upregulation of HSF1 in estrogen receptor positive breast cancer

  2016cited by this paper
• Molecular mechanism of thermosensory function of human heat shock transcription factor Hsf1

  2016cited by this paper
• Selective killing of cancer cells by small molecules targeting heat shock stress response.

  2016cited by this paper
• Fisetin, a dietary flavonoid, induces apoptosis of cancer cells by inhibiting HSF1 activity through blocking its binding to the hsp70 promoter.

  2015cited by this paper
• Heat shock factor 1 is a potent therapeutic target for enhancing the efficacy of treatments for multiple myeloma with adverse prognosis

  2015cited by this paper
• Phase I/II Study of HSP90 Inhibitor AUY922 and Erlotinib for EGFR-Mutant Lung Cancer With Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

  2015cited by this paper
• Minnelide, a novel drug for pancreatic and liver cancer.

  2015cited by this paper
• Phase I study of the heat shock protein 90 (Hsp90) inhibitor onalespib (AT13387) administered on a daily for 2 consecutive days per week dosing schedule in patients with advanced solid tumors

  2015cited by this paper
• Higher heat shock factor 1 expression in tumor stroma predicts poor prognosis in esophageal squamous cell carcinoma patients

  2015cited by this paper
• Hsp90 interaction with clients.

  2015cited by this paper
• ERK-dependent phosphorylation of HSF1 mediates chemotherapeutic resistance to benzimidazole carbamates in colorectal cancer cells

  2015cited by this paper
• Client Proteins and Small Molecule Inhibitors Display Distinct Binding Preferences for Constitutive and Stress-Induced HSP90 Isoforms and Their Conformationally Restricted Mutants

  2015cited by this paper
• NZ28-induced inhibition of HSF1, SP1 and NF-κB triggers the loss of the natural killer cell-activating ligands MICA/B on human tumor cells

  2015cited by this paper
• Uncoupling Stress-Inducible Phosphorylation of Heat Shock Factor 1 from Its Activation

  2015cited by this paper
• Inhibiting Heat Shock Factor 1 in Human Cancer Cells with a Potent RNA Aptamer

  2014influential reference
• A direct regulatory interaction between chaperonin TRiC and stress-responsive transcription factor HSF1.

  2014cited by this paper
• First-in-Human Phase I Dose Escalation Study of a Second-Generation Non-Ansamycin HSP90 Inhibitor, AT13387, in Patients with Advanced Solid Tumors

  2014cited by this paper
• The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy.

  2014cited by this paper
• HSF1 at a glance

  2014cited by this paper
• High level of HSF1 associates with aggressive endometrial carcinoma and suggests potential for HSP90 inhibitors

  2014cited by this paper
• Heat shock factor 1 accelerates hepatocellular carcinoma development by activating nuclear factor-κB/mitogen-activated protein kinase.

  2014cited by this paper
• Heat shock factor 1 is required for migration and invasion of human melanoma in vitro and in vivo.

  2014cited by this paper
• Proteostatic control of telomerase function through TRiC-mediated folding of TCAB1.

  2014cited by this paper
• Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK

  2014cited by this paper
• mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

  2014cited by this paper
• Tight Coordination of Protein Translation and HSF1 Activation Supports the Anabolic Malignant State

  2013cited by this paper
• Flavaglines: potent anticancer drugs that target prohibitins and the helicase eIF4A.

  2013cited by this paper
• Inhibition of Inducible Heat Shock Protein-70 (Hsp72) Enhances Bortezomib-Induced Cell Death in Human Bladder Cancer Cells

  2013cited by this paper
• Targeting HSF1 sensitizes cancer cells to HSP90 inhibition

  2013cited by this paper
• The heat shock transcription factor 1 as a potential new therapeutic target in multiple myeloma

  2013cited by this paper
• mTOR Is Essential for the Proteotoxic Stress Response, HSF1 Activation and Heat Shock Protein Synthesis

  2012cited by this paper
• Heat shock factor 1 promotes invasion and metastasis of hepatocellular carcinoma in vitro and in vivo

  2012cited by this paper
• Heat Shock Transcription Factor Hsf1 Is Involved in Tumor Progression via Regulation of Hypoxia-Inducible Factor 1 and RNA-Binding Protein HuR

  2012cited by this paper
• Heat Shock Factor Hsf1 Cooperates with ErbB2 (Her2/Neu) Protein to Promote Mammary Tumorigenesis and Metastasis*

  2012cited by this paper
• Hsp90 Molecular Chaperone Inhibitors: Are We There Yet?

  2012cited by this paper
• Tumor-intrinsic and tumor-extrinsic factors impacting hsp90- targeted therapy.

  2012cited by this paper
• HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers.

  2012influential reference
• Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis.

  2012cited by this paper
• Prosurvival role of heat shock factor 1 in the pathogenesis of pancreatobiliary tumors.

  2011cited by this paper
• High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer

  2011cited by this paper
• XPB, a subunit of TFIIH, is a target of the natural product triptolide.

  2011cited by this paper
• Heat shock transcription factor 1 is a key determinant of HCC development by regulating hepatic steatosis and metabolic syndrome.

  2011cited by this paper
• The heat shock response: systems biology of proteotoxic stress in aging and disease.

  2011cited by this paper
• The stress of protein misfolding: from single cells to multicellular organisms.

  2011cited by this paper
• KRIBB11 Inhibits HSP70 Synthesis through Inhibition of Heat Shock Factor 1 Function by Impairing the Recruitment of Positive Transcription Elongation Factor b to the hsp70 Promoter*

  2010influential reference
• RNA polymerase - an important molecular target of triptolide in cancer cells.

  2010cited by this paper
• Targeting the dynamic HSP90 complex in cancer

  2010cited by this paper
• Heat shock transcription factor HSF1 plays a critical role in HER2-induced cellular transformation and tumorigenesis

  2010cited by this paper
• Modulation of Hsf1 activity by novobiocin and geldanamycin.

  2009cited by this paper
• Triptolide-induced transcriptional arrest is associated with changes in nuclear substructure.

  2008cited by this paper
• Heat shock factor 1 represses estrogen-dependent transcription through association with MTA1

  2008cited by this paper
• Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis.

  2007influential reference
• Natively Unstructured Loops Differ from Other Loops

  2007cited by this paper
• Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70.

  2007cited by this paper
• Selective suppression of lymphomas by functional loss of Hsf1 in a p53-deficient mouse model for spontaneous tumors

  2007cited by this paper
• Targeting heat shock response to sensitize cancer cells to proteasome and Hsp90 inhibitors.

  2006cited by this paper
• An RNA aptamer that interferes with the DNA binding of the HSF transcription activator

  2006cited by this paper
• Triptolide, an Inhibitor of the Human Heat Shock Response That Enhances Stress-induced Cell Death*

  2006cited by this paper
• Analysis of phosphorylation of human heat shock factor 1 in cells experiencing a stress

  2005cited by this paper
• Transcriptional regulation and binding of heat shock factor 1 and heat shock factor 2 to 32 human heat shock genes during thermal stress and differentiation

  2004cited by this paper
• Regulation of Molecular Chaperone Gene Transcription Involves the Serine Phosphorylation, 14-3-3ε Binding, and Cytoplasmic Sequestration of Heat Shock Factor 1

  2003cited by this paper
• Benzylidene lactam compound, KNK437, a novel inhibitor of acquisition of thermotolerance and heat shock protein induction in human colon carcinoma cells.

  2000cited by this paper
• A new use for the 'wing' of the 'winged' helix-turn-helix motif in the HSF–DNA cocrystal

  1999cited by this paper
• Molecular chaperones as HSF1-specific transcriptional repressors.

  1998cited by this paper
• Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1.

  1998cited by this paper
• The regulatory domain of human heat shock factor 1 is sufficient to sense heat stress

  1996cited by this paper
• Multiple layers of regulation of human heat shock transcription factor 1

  1995cited by this paper
• The carboxyl-terminal transactivation domain of heat shock factor 1 is negatively regulated and stress responsive

  1995cited by this paper
• A heat shock-responsive domain of human HSF1 that regulates transcription activation domain function

  1995cited by this paper
• Regulation of heat shock factor trimer formation: role of a conserved leucine zipper.

  1993cited by this paper
• Stable binding of Drosophila heat shock factor to head-to-head and tail-to-tail repeats of a conserved 5 bp recognition unit.

  1989cited by this paper
• Yeast heat shock factor is an essential DNA-binding protein that exhibits temperature-dependent phosphorylation.

  1988cited by this paper
• The heat-shock response.

  1986cited by this paper

• Discovery and development of inhibitors of heat shock factor 1 by a fluorescence polarization assay

  2025cites this paper
• Small Molecules Targeting HSF1 Pathway: Chemical Strategies and Therapeutic Potential.

  2025cites this paper
• HSF1 Activation Mechanisms, Disease Roles, and Small Molecule Therapeutics

  2025cites this paper
• Supramolecular nanoagent as a dual-blocked thermoresistance inhibitor for effective mild-temperature photothermal therapy.

  2025cites this paper
• HSF1 at the crossroads of chemoresistance: from current insights to future horizons in cell death mechanisms

  2025cites this paper
• Targeting the heat shock response induced by modulated electro-hyperthermia (mEHT) in cancer.

  2024cites this paper
• The small-molecule drug homoharringtonine targets HSF1 to suppress pancreatic cancer progression.

  2024cites this paper
• PU-H71 (NSC 750424): a molecular masterpiece that targets HSP90 in cancer and beyond

  2024cites this paper
• Unraveling TRPV1’s Role in Cancer: Expression, Modulation, and Therapeutic Opportunities with Capsaicin

  2024cites this paper
• The cytotoxic activities of the major diterpene extracted from Salvia multicaulis (Bardakosh) are mediated by the regulation of heat-shock response and fatty acid metabolism pathways in human leukemia cells.

  2024cites this paper
• Pan-Cancer Single-Cell Analysis Revealing the Heterogeneity of Cancer-Associated Fibroblasts in Skin Tumors.

  2024cites this paper
• Monitoring of the Heat Shock Response with a Real-Time Luciferase Reporter.

  2023cites this paper
• Nanoparticle-mediated TRPV1 channel blockade amplifies cancer thermo-immunotherapy via heat shock factor 1 modulation

  2023cites this paper
• HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia

  2022cites this paper
• HSF1 promotes endometriosis development and glycolysis by up-regulating PFKFB3 expression

  2021cites this paper
• PLOD1 acts as a tumor promoter in glioma via activation of the HSF1 signaling pathway

  2021cites this paper
• Interplay between mammalian heat shock factors 1 and 2 in physiology and pathology

  2021cites this paper
• Role of heparanase 2 (Hpa2) in gastric cancer

  2021cites this paper
• Recent advances in heat shock proteins in cancer diagnosis, prognosis, metabolism and treatment.

  2021cites this paper
• Integrated Bioinformatics Analysis Identifies Heat Shock Factor 2 as a Prognostic Biomarker Associated With Immune Cell Infiltration in Hepatocellular Carcinoma

  2021influential citation
• A Driver Never Works Alone—Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer

  2020cites this paper
• HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity

  2020cites this paper
• Buxus alkaloid compound destabilizes mutant p53 through inhibition of the HSF1 chaperone axis.

  2020cites this paper
• HSF1 Promotes the Development of Endometriosis by Up-regulating PFKFB3 Expression

  2020cites this paper
• HSF2 is a Promising Prognostic Biomarker and is Correlated With Immune Infiltration in Hepatocellular Carcinoma

  2020cites this paper
• Targeting therapy-resistant prostate cancer via a direct inhibitor of the human heat shock transcription factor 1

  2020cites this paper
• Effects of LRP1B Regulated by HSF1 on Lipid Metabolism in Hepatocellular Carcinoma

  2020influential citation
• HSF1 Regulates Cellular Senescence: Role of the DHRS2-MDM2-p53 Pathway

  2020cites this paper
• Small Molecule Inhibitors Targeting Heat Shock Response Pathways: Lessons from Clinical and Preclinical Studies in Cancer Therapeutics

  2020cites this paper
• Emerging roles of HSF1 in cancer: Cellular and molecular episodes.

  2020cites this paper
• Combination of Anti-Cancer Drugs with Molecular Chaperone Inhibitors

  2019cites this paper
• Heat Shock Proteins Are Essential Components in Transformation and Tumor Progression: Cancer Cell Intrinsic Pathways and Beyond

  2019cites this paper
• What sustains the multidrug resistance phenotype beyond ABC efflux transporters? Looking beyond the tip of the iceberg.

  2019cites this paper