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

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.

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.