Targeting tumor proteostasis has emerged as a promising strategy in anticancer therapy, particularly through Hsp90 inhibition, which has shown clinical potential. However, the efficacy of Hsp90 inhibitors is limited by the activation of HSF1, a master regulator of the heat shock response (HSR), which mitigates proteotoxic stress by inducing protective chaperones. To address this limitation, we investigated the role of HSF1 SUMOylation in modulating its activity and its impact on Hsp90 inhibitor efficacy. We generated HSF1 mutants with lysine-to-arginine substitutions at five SUMOylation sites and studied their function in H1299 lung carcinoma cells with HSF1/HSF2 knockout, which lack a functional HSR. Unexpectedly, these mutants retained full transcriptional activity during the early phase of the heat shock response, mimicking the initial stress response of wild-type HSF1. SUMOylation inhibition using Subasumstat also led to altered nuclear stress bodies morphology but did not impair Hsp70 induction or enhance Hsp90 inhibitor cytotoxicity. Our findings reveal that SUMOylation is dispensable for HSF1 activation and transactivation capacity during the early phase of HSR. These results refine our understanding of HSF1 regulation and suggest that alternative strategies targeting HSF1 stability and degradation may enhance the therapeutic efficacy of proteostasis-targeting cancer therapies.

• Klíčová slova
• Cancer, HSF1, Heat shock response, SUMOylation, Stress, Subasumstat,
• MeSH
• aktivace transkripce * MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• proteiny tepelného šoku HSP90 metabolismus   antagonisté a inhibitory   MeSH
• reakce na tepelný šok * genetika   MeSH
• sumoylace * MeSH
• transkripční faktory tepelného šoku * metabolismus   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• HSF1 protein, human MeSH Prohlížeč
• proteiny tepelného šoku HSP90 MeSH
• transkripční faktory tepelného šoku * MeSH

Heat shock factor 1 (HSF1) is the master orchestrator of the heat shock response (HSR), a critical process for maintaining cellular health and protein homeostasis. These effects are achieved through rapid expression of molecular chaperones, the heat shock proteins (HSPs), which ensure correct protein folding, repair, degradation and stabilization of multiprotein complexes. In addition to its role in the HSR, HSF1 influences the cell cycle, including processes such as S phase progression and regulation of the p53 pathway, highlighting its importance in cellular protein synthesis and division. While HSF1 activity offers neuroprotective benefits in neurodegenerative diseases, its proteome-stabilizing function may also reinforce tumorigenic transformation. HSF1 overexpression in many types of cancer reportedly enhances cell growth enables survival, alters metabolism, weakens immune response and promotes angiogenesis or epithelial-mesenchymal transition (EMT) as these cells enter a form of "HSF1 addiction". Furthermore, the client proteins of HSF1-regulated chaperones, particularly Hsp90, include numerous key players in classical tumorigenic pathways. HSF1 thus presents a promising therapeutic target for cancer treatment, potentially in combination with HSP inhibitors to alleviate typical initiation of HSR upon their use.

• Klíčová slova
• Cancer, Cell division, HSF1, HSR, Heat shock, Protein homeostasis,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH