Heat shock factor 1 (HSF1) plays a central role in orchestrating the heat shock response (HSR), leading to the activation of multiple heat shock proteins (HSPs) genes and approximately thousands of other genes involved in various cellular functions. In cancer cells, HSPs play a particular role in coping with the accumulation of damaged proteins resulting from dysregulated translation and post-translational processes. This proteotoxic stress is a hallmark of cancer cells and causes constitutive activation of HSR. Beyond its role in the HSR, HSF1 regulates diverse processes critical for tumor cells, including proliferation, cell death, and drug resistance. Emerging evidence also highlights HSF1’s involvement in remodeling the tumor immune microenvironment as well as in the maintenance of cancer stem cells. Consequently, HSF1 has emerged as an attractive therapeutic target, prompting the development of specific HSF1 inhibitors that have progressed to clinical trials. Importantly, HSF1 possesses a broad interactome, forming protein–protein interactions (PPIs) with components of signaling pathways, transcription factors, and chromatin regulators. Many of these interactors modulate HSF1’s activity and HSF1-dependent gene expression and are well-recognized targets for cancer therapy. This review summarizes the current knowledge on HSF1 interactions with molecular chaperones, protein kinases, and other regulatory proteins. Understanding the key HSF1 interactions promoting cancer progression, along with identifying factors that disrupt these protein complexes, may offer valuable insights for developing innovative therapeutic strategies against cancer.
热休克因子1（HSF1）在协调热休克反应（HSR）中发挥核心作用，能够激活多种热休克蛋白（HSP）基因以及涉及多种细胞功能的约数千个其他基因。在癌细胞中，热休克蛋白尤其应对因翻译及翻译后过程失调导致的受损蛋白积累。这种蛋白毒性应激是癌细胞的标志性特征，并导致热休克反应的持续激活。除调控热休克反应外，HSF1还参与调节肿瘤细胞增殖、细胞死亡及耐药性等关键过程。最新研究还表明HSF1参与重塑肿瘤免疫微环境及维持癌症干细胞。因此，HSF1已成为极具吸引力的治疗靶点，推动特异性HSF1抑制剂的研发并已进入临床试验阶段。值得注意的是，HSF1具有广泛的相互作用网络，能与信号通路组分、转录因子及染色质调控因子形成蛋白质-蛋白质相互作用（PPIs）。其中许多相互作用因子可调节HSF1活性及其依赖的基因表达，且已被公认为癌症治疗靶点。本综述总结了当前关于HSF1与分子伴侣、蛋白激酶及其他调控蛋白相互作用的研究进展。深入理解促进癌症进展的关键HSF1相互作用机制，并识别破坏这些蛋白质复合物的因素，可能为开发创新性癌症治疗策略提供重要启示。
Unveiling the HSF1 Interaction Network: Key Regulators of Its Function in Cancer
肿瘤(癌症)患者之家