Heat Shock Factor 1 (HSF1) is the master stress transcription factor which enables cells to overcome and survive otherwise lethal stresses (heat, acidosis, hypoxia, genomic stress, oxidative stress, etc.) [1-3]. While central to several pathophysiological conditions, in cancer cells, HSF1 is intimately linked with cancer initiation, progression and metastasis [2, 4, 5]. Consistent with major involvement in metastasis, HSF1 is highly expressed and activated in high grade primary cancers, significantly increased in metastatic lesions and strongly associated with poor outcomes in cancer patients (lung, breast, prostate, etc) [6-8].
While HSF1 has been demonstrated to be dispensable for normal function and survival (in both cell and whole animal models), in advanced cancer cells HSF1 knockdown induces lethality [4, 9]. HSF1 has consequently emerged as a major therapeutic target, and this has motivated numerous research groups to undertake programs which seek to develop HSF1 inhibitors [2, 10, 11]. However, to this end these have been unsuccessful due to an inability to specifically and directly target HSF1 (thus resulting in non-specific modes of action) [2, 10, 11]. We have taken an alternative approach to targeting HSF1, through the development of rationally designed peptide inhibitors.
In this study, we have confirmed that our peptide inhibitor (HiPe4) directly binds HSF1 through use of a biotinylated pulldown of recombinant HSF1. We have also demonstrated that HiPe4 (through incorporation of cell permeability sequences) reduces levels of cell motility proteins and proteins directly regulated by HSF1. Importantly, other proteins not under direct HSF1 regulation have been shown to be unaffected by HiPe4.
The outcomes of this work provide essential preliminary data establishing the efficacy of HiPe4 for interacting with HSF1 and inhibiting its function in vitro, prior to further investigations we will conduct in vivo.