INSERM, LNC UMR1231, Team GAD, University of Burgundy and Franche-Comté, F-21000, Dijon, France; FHU-TRANSLAD, University of Burgundy and Franche-Comté, Dijon University Hospital, F-21000, Dijon, France.
INSERM, LNC UMR1231 Team HSP-pathies, University of Burgundy and Franche-Comté, F-21000, Dijon, France.
Biochem Biophys Res Commun. 2020 Sep 24;530(3):520-526. doi: 10.1016/j.bbrc.2020.04.146. Epub 2020 Jun 30.
PIK3CA-related overgrowth spectrum is caused by mosaicism mutations in the PIK3CA gene. These mutations, which are also observed in various types of cancer, lead to a constitutive activation of the PI3K/AKT/mTOR pathway, increasing cell proliferation. Heat shock transcription factor 1 (HSF1) is the major stress-responsive transcription factor. Recent findings indicate that AKT phosphorylates and activates HSF1 independently of heat-shock in breast cancer cells. Here, we aimed to investigate the role of HSF1 in PIK3CA-related overgrowth spectrum. We observed a higher rate of proliferation and increased phosphorylation of AKT and p70S6K in mutant fibroblasts than in control cells. We also found elevated phosphorylation and activation of HSF1, which is directly correlated to AKT activation. Specific AKT inhibitors inhibit HSF1 phosphorylation as well as HSF1-dependent gene transcription. Finally, we demonstrated that targeting HSF1 with specific inhibitors reduced the proliferation of mutant cells. As there is currently no curative treatment for PIK3CA-related overgrowth spectrum, our results identify HSF1 as a new potential therapeutic target.
PIK3CA 相关过度生长谱是由 PIK3CA 基因突变引起的嵌合体突变引起的。这些突变也存在于各种类型的癌症中，导致 PI3K/AKT/mTOR 通路的组成性激活，从而增加细胞增殖。热休克转录因子 1（HSF1）是主要的应激反应转录因子。最近的研究结果表明，AKT 在乳腺癌细胞中独立于热休克磷酸化和激活 HSF1。在这里，我们旨在研究 HSF1 在 PIK3CA 相关过度生长谱中的作用。我们观察到突变型成纤维细胞的增殖率较高，AKT 和 p70S6K 的磷酸化水平也升高。我们还发现 HSF1 的磷酸化和激活水平升高，这与 AKT 的激活直接相关。特异性 AKT 抑制剂可抑制 HSF1 的磷酸化以及 HSF1 依赖性基因转录。最后，我们证明了用特异性抑制剂靶向 HSF1 可降低突变细胞的增殖。由于目前尚无针对 PIK3CA 相关过度生长谱的治愈性治疗方法，我们的研究结果表明 HSF1 是一个新的潜在治疗靶点。
