Shock about heat shock in cancer

摘要: The transcription factor heat shock 1 (HSF1) is the master regulator of response. It crucial for cell homeostasis and implicated in aging, neurodegenerative disease cancer [1]. Although induction by HSF1 expression molecular chaperones other regulators protein quality control, both folding degradation, well established, precise detailed transcriptional network that regulates poorly understood. An important new study identifies an HSF1-regulated program highly malignant cells surprisingly distinct from traditional response [2]. results have significant implications our understanding development therapies. The response, mediated activation HSF1, ancient, conserved mechanism protects organisms against various adverse environmental pathological conditions damage cellular proteins [3]. In cancer, such proteotoxic stress caused accumulation mutated proteins, aneuploidy, reactive oxygen species challenging tumor microenvironment (eg hypoxia, low pH), which must counteract activating to survive [4, 5]. In healthy, non-stressed cells, located cytoplasm inhibitory complex with chaperone 90 (HSP90) – another key player proteostasis progression. Upon as classically induced shock, dissociates HSP90, trimerizes, translocates nucleus associates its cognate DNA sequence localized at promoters target genes modulate their (Figure ​(Figure1).1). tightly regulated many post-translational modifications, including phosphorylation, sumoylation acetylation, pattern extent varies depending on nature intensity [3]. Figure 1 Distinct overlapping are when versus stresses Deregulated a vulnerability, exploitable targeting degradation. proteasome inhibitor bortezomib (approved multiple myeloma) HSP90 inhibitors (showing promise breast non small lung cancer) enhance causing cycle arrest apoptosis. However, efficacy limited hence numerous cytoprotective like HSP70 family members ameliorate proteostatic damage, drug resistance [6-8]. Accumulating evidence shows critically involved oncogenesis. Key studies using HSF1-knockout mice demonstrate requirement tumorigenesis oncogenic RAS or mutant P53 [9]. Furthermore, silencing blocks proliferation survival driven diverse factors. supports phenotype promoting signal transduction pathways, proliferation, survival, synthesis glucose metabolism Thus not only critical regulation stress, but also driver potential therapeutic [10, 11]. The common view effects oncogenesis via increased HSP oncogenic-support properties [10]. Medillo et al. now rewires transcriptome surprising way one quite classical response. First, al up-regulated constitutively activated shown nuclear localization phosphorylation serine 326 oncogene-transformed tumorigenic metastatic, compared less isogenic counterparts. Also, most aggressive lines more dependent growth indicating stronger ‘addiction’ vulnerability. Next, use chromatin immunoprecipitation linked next-generation sequencing (ChIP-Seq) identify bound HSF1. Under basal binds immortalized non-transformed cells. Binding occurs promoter regions distal sites. Following binding enhanced all lines. Surprisingly, however, there marked differences under normal following shock. Many specifically enrichment translation, RNA binding, adhesion. Examples cancer-specific highlighted include CKS2 encoding cyclin-dependent kinase interacting protein; LY6K coding glycophosphatidyl-inositol-anchored membrane connections; RBM23 RNA-binding estrogen-mediated transcription. On hand, set those after indicate interesting level overlap between gene signature thermal associated malignancy raising possibility different mechanisms epigenetic modifications) may be preferentially these two stress-activating Importantly, interference confirm role regulating identified genes. Following on, occupancy profile origins breast, colon lung. Of high translational significance, they then ChIP-Seq HSF1-mediated active tumors obtained directly human patients. Finally direct clinical relevance, ‘HSF1-cancer signature’ comprising 456 cancer-regulated poor outcome cancers predictive than commonly used prognostic markers MYC, Ki67 MammaPRINT signature. This provides much clearer progression metastatic state food thought future research. Most specific rewiring work highlights complexity function. Differences could reflect disparities amount present result deregulation several pathways EGFR/HER2, RAS/MAPK insulin/IGF1) and/or states. In addition basic research consequences. Understanding functional relevance factors modifications activity, identifying cofactors likely provide biomarkers novel ways efficiently Figure ​Figure1)1) megalomaniac played malignancy. Thus, although has been around billion years evolution, it continues surprise us. near we will very see shocks about cancer.