Vladimirova Snezhana A, Kokoreva Nadezhda E, Guzhova Irina V, Alhasan Bashar A, Margulis Boris A, Nikotina Alina D
Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064 St. Petersburg, Russia.
Cancers (Basel). 2024 Nov 30;16(23):4030. doi: 10.3390/cancers16234030.
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）中起核心作用，导致多种热休克蛋白（HSPs）基因以及大约数千个参与各种细胞功能的其他基因被激活。在癌细胞中，HSPs在应对翻译失调和翻译后过程导致的受损蛋白质积累方面发挥着特殊作用。这种蛋白毒性应激是癌细胞的一个标志，并导致HSR的组成性激活。除了在HSR中的作用外，HSF1还调节对肿瘤细胞至关重要的多种过程，包括增殖、细胞死亡和耐药性。新出现的证据还强调了HSF1参与重塑肿瘤免疫微环境以及维持癌症干细胞。因此，HSF1已成为一个有吸引力的治疗靶点，促使开发已进入临床试验阶段的特异性HSF1抑制剂。重要的是，HSF1拥有广泛的相互作用组，与信号通路的组成部分、转录因子和染色质调节因子形成蛋白质-蛋白质相互作用（PPIs）。许多这些相互作用蛋白调节HSF1的活性和HSF1依赖性基因表达，并且是公认的癌症治疗靶点。本综述总结了目前关于HSF1与分子伴侣、蛋白激酶和其他调节蛋白相互作用的知识。了解促进癌症进展的关键HSF1相互作用，以及识别破坏这些蛋白质复合物的因素，可能为开发创新的癌症治疗策略提供有价值的见解。
