Chemical Biology Approaches to Interrogate Heat Shock Transcription Factor 1 Regulation in Cancer
Heat Shock transcription Factor 1 (HSF1) has long been recognized as the master regulator and signal integrator in the eukaryotic proteotoxic stress response. Revealed by recent discoveries in cancer, the functions of HSF1 have extended far beyond its canonical role in protein folding, further encompassing critical functions in anti-apoptosis, invasion and metastasis, energy metabolism, DNA damage repair, and evasion of host immune surveillance. Meanwhile, both our understanding of the molecular basis of HSF1 regulation as well as available biochemical tools to investigate such details are lacking. Based on an in vitro ligand binding approach, the studies presented in this thesis were dedicated to the identification, validation, and characterization of a direct, first-in-class, small-molecule HSF1 inhibitor. The pharmacological inhibition of HSF1 occurs through small-molecule stimulation of nuclear, but not cytoplasmic HSF1 degradation, which attenuated prostate cancer cell proliferation, inhibited the HSF1 cancer gene signature and arrested tumor progression in multiple therapy-resistant animal models of prostate cancer. The identification of a direct small-molecule HSF1 inhibitor provides a unique pharmacological tool for future HSF1 research and serves as a significant proof-of-concept for pharmacologically targeting HSF1 for anti-cancer treatment approaches.
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