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Inhibition of TRPM7 blocks MRTF/SRF-dependent transcriptional and tumorigenic activity

Oncogene volume 39, pages 2328–2344 (2020)Cite this article

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Abstract

Myocardin-related transcription factors A and B (MRTFs) are coactivators of Serum Response Factor (SRF) that mediates the expression of genes involved in cell proliferation, migration and differentiation. There is mounting evidence that MRTFs and SRF represent promising targets for hepatocellular carcinoma (HCC) growth. Since MRTF-A nuclear localization is a prerequisite for its transcriptional activity and oncogenic properties, we searched for pharmacologically active compounds able to redistribute MRTF-A to the cytoplasm. We identified NS8593, a negative gating modulator of the transient receptor potential cation channel TRPM7, as a novel inhibitor of MRTF-A nuclear localization and transcriptional activity. Using a pharmacological approach and targeted genome editing, we investigated the functional contribution of TRPM7, a unique ion channel containing a serine-threonine kinase domain, to MRTF transcriptional and tumorigenic activity. We found that TRPM7 function regulates RhoA activity and subsequently actin polymerization, MRTF-A-Filamin A complex formation and MRTF-A/SRF target gene expression. Mechanistically, TRPM7 signaling relies on TRPM7 channel-mediated Mg2+ influx and phosphorylation of RhoA by TRPM7 kinase. Pharmacological blockade of TRPM7 results in oncogene-induced senescence of hepatocellular carcinoma (HCC) cells in vitro and in vivo in HCC xenografts. Hence, inhibition of the TRPM7/MRTF axis emerges as a promising strategy to curb HCC growth.

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Fig. 1: Redistribution of MRTF-A to the cytoplasm and inhibition of SRF target gene expression upon TRPM7 blockade.
Fig. 2: Inhibition of MRTF/SRF target gene expression upon TRPM7 blockade.
Fig. 3: Inactivation of the RhoA/actin signaling axis upon TRPM7 blockade.
Fig. 4: Functional coupling of RhoA and TRPM7 via its kinase domain.
Fig. 5: Requirement of TRPM7 kinase activity for MRTF transcriptional activity.
Fig. 6: TRPM7 blockade results in oncogene-induced senescence.
Fig. 7: Antitumor effects of TRPM7 blockade in vivo.
Fig. 8: Model for MRTF-A regulation upon TRPM7 blockade.

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Acknowledgements

Funded by grant MU 2737/2-2 and Research Training Group 2338 of the Deutsche Forschungsgemeinschaft. TG, VC, and SZ were supported by Transregional Collaborative Research Center 152. We thank Margarete Goppelt-Struebe for critical reading of the manuscript and Sarah Hampe and Philip Riemenschneider for technical assistance.

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Author notes

  1. Laura Schreyer, Melanie A. Meier & Susanne Muehlich

    Present address: Department of Chemistry and Pharmacy, Molecular and Clinical Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

  2. These authors contributed equally: Thomas Gudermann, Susanne Muehlich

Authors and Affiliations

  1. Walther-Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Munich, Germany

    Sandra Voringer, Laura Schreyer, Wiebke Nadolni, Melanie A. Meier, Katharina Woerther, Constanze Mittermeier, Silvia Ferioli, Susanna Zierler, Vladimir Chubanov, Thomas Gudermann & Susanne Muehlich

  2. Institute of Pathology, University Medicine Greifswald, Greifswald, Germany

    Stephan Singer & Kerstin Holzer

  3. LGL Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, Oberschleißheim, Germany

    Bernhard Liebl

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Voringer, S., Schreyer, L., Nadolni, W. et al. Inhibition of TRPM7 blocks MRTF/SRF-dependent transcriptional and tumorigenic activity. Oncogene 39, 2328–2344 (2020). https://doi.org/10.1038/s41388-019-1140-8

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