Multifaceted roles of HSF1 in cell death: A state-of-the-art review.

Cell death is a common and active process that is involved in various biological processes, including organ development, morphogenesis, maintaining tissue homeostasis and eliminating potentially harmful cells. Abnormal regulation of cell death significantly contributes to tumor development, progression and chemoresistance. The mechanisms of cell death are complex and involve not only apoptosis and necrosis but also their cross-talk with other types of cell death, such as autophagy and the newly identified ferroptosis. Cancer cells are chronically exposed to various stresses, such as lack of oxygen and nutrients, immune responses, dysregulated metabolism and genomic instability, all of which lead to activation of heat shock factor 1 (HSF1). In response to heat shock, oxidative stress and proteotoxic stresses, HSF1 upregulates transcription of heat shock proteins (HSPs), which act as molecular chaperones to protect normal cells from stresses and various diseases. Accumulating evidence suggests that HSF1 regulates multiple types of cell death through different signaling pathways as well as expression of distinct target genes in cancer cells. Here, we review the current understanding of the potential roles and molecular mechanism of HSF1 in regulating apoptosis, autophagy and ferroptosis. Deciphering HSF1-regulated signaling pathways and target genes may help in the development of new targeted anti-cancer therapeutic strategies.

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