n2-(1h-indazole-5-yl)-n6-methyl-3-nitropyridine-2-6-diamine and Breast-Neoplasms

Heat shock transcription factor 1 (HSF1) is the master regulator of the proteotoxic stress response, which plays a key role in breast cancer tumorigenesis. However, the mechanisms underlying regulation of HSF1 protein stability are still unclear. Here, we show that HSF1 protein stability is regulated by PIM2-mediated phosphorylation of HSF1 at Thr120, which disrupts the binding of HSF1 to the E3 ubiquitin ligase FBXW7. In addition, HSF1 Thr120 phosphorylation promoted proteostasis and carboplatin-induced autophagy. Interestingly, HSF1 Thr120 phosphorylation induced HSF1 binding to the PD-L1 promoter and enhanced PD-L1 expression. Furthermore, HSF1 Thr120 phosphorylation promoted breast cancer tumorigenesis

Topics: Aminopyridines; Animals; Autophagy; B7-H1 Antigen; Benzylidene Compounds; Breast Neoplasms; Carboplatin; F-Box-WD Repeat-Containing Protein 7; Female; Gene Expression Regulation, Neoplastic; Heat Shock Transcription Factors; Humans; Indazoles; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Neoplasm Proteins; Phosphorylation; Protein Binding; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Stability; Proto-Oncogene Proteins; RNA Interference; RNA, Small Interfering; Substrate Specificity; Thiazolidinediones; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays