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The proteostasis guardian HSF1 directs the transcription of its paralog and interactor HSF2 during proteasome dysfunction

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Abstract

Protein homeostasis is essential for life in eukaryotes. Organisms respond to proteotoxic stress by activating heat shock transcription factors (HSFs), which play important roles in cytoprotection, longevity and development. Of six human HSFs, HSF1 acts as a proteostasis guardian regulating stress-induced transcriptional responses, whereas HSF2 has a critical role in development, in particular of brain and reproductive organs. Unlike HSF1, that is a stable protein constitutively expressed, HSF2 is a labile protein and its expression varies in different tissues; however, the mechanisms regulating HSF2 expression remain poorly understood. Herein we demonstrate that the proteasome inhibitor anticancer drug bortezomib (Velcade), at clinically relevant concentrations, triggers de novo HSF2 mRNA transcription in different types of cancers via HSF1 activation. Similar results were obtained with next-generation proteasome inhibitors ixazomib and carfilzomib, indicating that induction of HSF2 expression is a general response to proteasome dysfunction. HSF2-promoter analysis, electrophoretic mobility shift assays, and chromatin immunoprecipitation studies unexpectedly revealed that HSF1 is recruited to a heat shock element located at 1.397 bp upstream from the transcription start site in the HSF2-promoter. More importantly, we found that HSF1 is critical for HSF2 gene transcription during proteasome dysfunction, representing an interesting example of transcription factor involved in controlling the expression of members of the same family. Moreover, bortezomib-induced HSF2 was found to localize in the nucleus, interact with HSF1, and participate in bortezomib-mediated control of cancer cell migration. The results shed light on HSF2-expression regulation, revealing a novel level of HSF1/HSF2 interplay that may lead to advances in pharmacological modulation of these fundamental transcription factors.

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Acknowledgments

The authors thank G. Zupi (Regina Elena Cancer Institute, Rome, Italy) for providing the M10 melanoma cell line, R. Piva (University of Turin, Italy) for KMM-1 multiple myeloma cells and S. Calderwood (Harvard Medical School, Boston, MA) for the Flag-HSF1-pcDNA3 expression vector. We also thank E. Romano (Center for Advanced Microscopy, University of Rome Tor Vergata) for assistance with confocal microscopy.

Funding

This work was supported by grants from the Italian Ministry of University and Scientific Research (PRIN project N 2010PHT9NF-006).

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  1. Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133, Rome, Italy

    Silvia Santopolo, Anna Riccio & M. Gabriella Santoro

  2. Institute of Translational Pharmacology, CNR, Rome, Italy

    Antonio Rossi & M. Gabriella Santoro

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  1. Silvia Santopolo
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S.S. performed the study on HSF2 transcription and ChIP analysis; S.S. and A. Rossi performed DNA-binding activity assays; S.S. and A. Riccio performed silencing experiments and analysis of cell survival; A. Riccio and A. Rossi generated stable HSF1-silenced cell lines; S.S. performed the study on cancer cell migration; M.G.S. designed the study; M.G.S. and S.S. wrote the manuscript. All authors contributed to the interpretation of the data and approve the content of the manuscript.

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Correspondence to M. Gabriella Santoro.

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Santopolo, S., Riccio, A., Rossi, A. et al. The proteostasis guardian HSF1 directs the transcription of its paralog and interactor HSF2 during proteasome dysfunction. Cell. Mol. Life Sci. 78, 1113–1129 (2021). https://doi.org/10.1007/s00018-020-03568-x

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