Collectively, these metabolic alterations in the absence of HSF1 activity reveal cancer cell liabilities and have a profound negative impact on T-ALL progression.
Using 10,287 cancer genomes from The Cancer Genome Atlas and Cbioportal databases, we assessed the association of HSF1 expression with CNA and cancer prognosis.
HSF1 appears to have a pleiotropic role in cancer by supporting multiple facets of malignancy including migration, invasion, proliferation, and cancer cell metabolism among others.
This surprising adaptive change in the stress response has additional implications for aging and chronic physiological stress that might explain an age-dependent dichotomy of HSF1 protein levels that are low in neurodegeneration and elevated in cancer.
We review the roles of HSF1 in cancer, its potential as a prognostic indicator for cancer treatment, evaluate current HSF1 inhibitors and provide guidelines for the identification of selective HSF1 inhibitors as chemical probes and for clinical development.
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.
Considering the role played by the heat shock protein of 70 kDa (HSP70) in cancer, we characterized this protein and its major regulator, the heat shock factor 1 (HSF1), in chronic lymphocytic leukemia (CLL).
Dorsomorphin is an HSF1 inhibitor.It induces cancer cell apoptosis, sensitizes cancer cells to both HSP90 and proteasome inhibitors, and suppresses HSP upregulation by these drugs, which may prevent the development of drug resistance.
Accumulating evidence reveals however that HSF1 participates in several other physiological and pathological processes such as differentiation, immune response, and multidrug resistance, as well as in ageing, neurodegenerative demise, and cancer.
The novel anti-HSF1 small-molecule inhibitors CCT251236 and KRIB11 demonstrate <i>in vitro</i> and <i>in vivo</i> antimyeloma activity, representing a novel approach for targeting the heat shock response in myeloma.<i>Clin Cancer Res; 24(10); 2237-8.
Therefore, we assessed HSF1 as a general sensor of proteotoxic stress and correlated its activity with sensitivity to three separate small molecule Hsp90 inhibitors in seven breast cancer cell lines representing each of the different cancer subtypes.
Receiver operating characteristic (ROC) analysis suggested that AAbs against HSF1 provided better detection of early-stage malignancy than CA125 alone.
Pharmacologic inhibition induced tumor growth inhibition and was well-tolerated in a human myeloma xenograft murine model with evidence of pharmacodynamic biomarker modulation.<b>Conclusions:</b> Taken together, our studies demonstrate the dependence of myeloma cells on HSF1 for survival and support the clinical evaluation of pharmacologic inhibitors of the HSF1 pathway in myeloma.<i>Clin Cancer Res; 24(10); 2395-407.
Through controlling these targets, HSF1 acts in diverse stress-induced cellular processes and molecular mechanisms, including the endoplasmic reticulum unfolded protein response and ubiquitin-proteasome system, multidrug resistance, autophagy, apoptosis, immune response, cell growth arrest, differentiation underlying developmental diapause, chromatin remodelling, cancer development, and ageing.
By suppressing tumour-suppressive amyloidogenesis, HSF1 preserves cancer proteostasis to support the malignant state, both providing insight into how HSF1 enables tumorigenesis and suggesting disruption of cancer proteostasis as a therapeutic strategy.
When HSF1 or BIS knockdown was combined with temozolomide (TMZ) treatment, a standard drug used in glioblastoma therapy, apoptosis increased, as measured by an increase in poly (ADP-ribose) polymerase (PARP) cleavage, whereas cancer stem-like properties, such as colony-forming activity and SOX2 protein expression, decreased.