Multifaceted Roles of Heat Shock Factor 1 (HSF 1) in Cancer
Introduction Heat shock proteins (HSPs) are molecular chaperones, which facilitate protein folding, trafficking, and proteasomal degradation. As the master regulator of the evolutionarily conserved heat-shock, or proteotoxic stress, response, heat shock f
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Abstract Introduction Heat shock proteins (HSPs) are molecular chaperones, which facilitate protein folding, trafficking, and proteasomal degradation. As the master regulator of the evolutionarily conserved heat-shock, or proteotoxic stress, response, heat shock factor 1 (HSF1) governs the stress-inducible HSP expression transcriptionally, thereby guarding proteomic stability and promoting cell survival of proteotoxic stress. This cytoprotective mechanism, however, is hijacked by cancer cells to alleviate intrinsic, chronic proteotoxic stress and support their malignant growth. Methods A narrative review of publications investigating the role of HSF1 in cancer was conducted. Results The literature review revealed that distinct from its inducible and transient activation by environmental stressors, HSF1 becomes constitutively active via diverse mechanisms within cancerous cells. Moreover, the pro-oncogenic roles of HSF1 appear to be multifaceted, beyond safeguarding the proteome, including enhancing survival, reprogramming metabolism, evoking genomic instability, and even promoting immune evasion. Importantly, unlike primary cells, cancerous cells highly depend on HSF1 for their growth and survival, a phenomenon referred to as “Non-oncogene Addiction”. Conclusions In contrast to its widely acclaimed cytoprotective role under stressful conditions, HSF1 acts as a potent pro-oncogenic factor. Besides being a valuable prognostic marker, emerging evidence supports HSF1 as a promising target for anticancer therapies.
M. Xu (*) · C. Dai (*) Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer InstituteFrederick, Frederick, MD, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2020 A. A. A. Asea, P. Kaur (eds.), Heat Shock Proteins, https://doi.org/10.1007/7515_2020_3
M. Xu and C. Dai
Keywords HSF1 · HSF1 inhibitor · HSP · Oncogenesis · Proteomic stability · Transcription independent
Abbreviations APC complex AR CAFs CaMKII EMT HCC HSF HSP HSR MSR PLK1 PSR RNAi
anaphase-promoting complex androgen receptor cancer-associated fibroblasts calcium/calmodulin-dependent protein kinase II epithelial-mesenchymal transition hepatocellular carcinoma heat shock factor heat shock proteins heat shock response metabolic stress response Polo-like kinase1 proteotoxic stress response RNA interference
1 Introduction Organisms inevitably encounter a wide array of environmental insults. In turn, environmental insults provoke diverse biological stresses, including genotoxic, oxidative, metabolic, and proteotoxic, to the cells. To cope with these stresses, specific cellular responses are promptly initiated to maintain the cellular homeostasis and, ultimately, the fitness of organisms. Among these diverse responses is the heatshock, or proteotoxic stress, response (HSR/PSR), one of the most evolutionarily conserved cytoprotective mechanisms [56]. Following exposure to heat stress, cells increase the induction of a group of heat shock proteins (HSPs) to prevent protein misfolding and
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