Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-102 Gliwice, Poland.
Department of Systems Biology and Engineering, Silesian University of Technology, Akademicka 16, 44-100 Gliwice, Poland.
Cells. 2022 Aug 12;11(16):2510. doi: 10.3390/cells11162510.
Heat Shock Factor 1 (HSF1), a transcription factor frequently overexpressed in cancer, is activated by proteotoxic agents and participates in the regulation of cellular stress response. To investigate how HSF1 level affects the response to proteotoxic stress, we integrated data from functional genomics analyses performed in MCF7 breast adenocarcinoma cells. Although the general transcriptional response to heat shock was impaired due to HSF1 deficiency (mainly chaperone expression was inhibited), a set of genes was identified, including and certain and family members, whose stress-induced activation was stronger and persisted longer than in cells with normal HSF1 levels. These genes were direct HSF1 targets, suggesting a dual (activatory/suppressory) role for HSF1. Moreover, we found that heat shock-induced inflammatory response could be stronger in HSF1-deficient cells. Analyses of The Cancer Genome Atlas data indicated that higher , , and expression levels correlated with low HSF1 levels in estrogen receptor-positive breast cancer, reflecting higher heat shock-induced expression of these genes in HSF1-deficient MCF7 cells observed in vitro. However, differences between the analyzed cancer types were noted in the regulation of HSF1-dependent genes, indicating the presence of cell-type-specific mechanisms. Nevertheless, our data indicate the existence of the heat shock-induced network of transcription factors (associated with the activation of TNFα signaling) which includes HSF1. Independent of its chaperone-mediated cytoprotective function, HSF1 may be involved in the regulation of this network but prevents its overactivation in some cells during stress.
热休克因子 1（HSF1）是一种在癌症中经常过表达的转录因子，它被蛋白毒性试剂激活，并参与细胞应激反应的调节。为了研究 HSF1 水平如何影响对蛋白毒性应激的反应，我们整合了在 MCF7 乳腺腺癌细胞中进行的功能基因组学分析的数据。尽管由于 HSF1 缺乏导致一般热休克反应受损（主要是伴侣蛋白表达受到抑制），但一组基因被鉴定出来，包括 和某些 和 家族成员，它们的应激诱导激活比具有正常 HSF1 水平的细胞更强且持续时间更长。这些基因是 HSF1 的直接靶基因，表明 HSF1 具有双重（激活/抑制）作用。此外，我们发现 HSF1 缺陷细胞中的热休克诱导的炎症反应可能更强。对癌症基因组图谱数据的分析表明，在雌激素受体阳性乳腺癌中，更高的 、 和 表达水平与 HSF1 水平降低相关，反映了体外观察到的 HSF1 缺陷 MCF7 细胞中这些基因的热休克诱导表达更高。然而，在所分析的癌症类型中，HSF1 依赖性基因的调节存在差异，表明存在细胞类型特异性机制。尽管如此，我们的数据表明存在热休克诱导的转录因子网络（与 TNFα 信号转导的激活相关），其中包括 HSF1。独立于其伴侣介导的细胞保护功能，HSF1 可能参与该网络的调节，但在某些细胞在应激期间防止其过度激活。
