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Theranostics 2019; 9(5):1490-1509. doi:10.7150/thno.29546 This issue Cite

Research Paper

Drug Repositioning Inferred from E2F1-Coregulator Interactions Studies for the Prevention and Treatment of Metastatic Cancers

Deborah Goody^1*, Shailendra K. Gupta^2*, David Engelmann¹, Alf Spitschak¹, Stephan Marquardt¹, Stefan Mikkat³, Claudia Meier¹, Charlotte Hauser⁴, Jan-Paul Gundlach⁴, Jan-Hendrik Egberts⁴, Hubert Martin⁵, Toni Schumacher¹, Anna Trauzold⁴, Olaf Wolkenhauer², Stella Logotheti¹, Brigitte M. Pützer^1,6✉

1. Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany;
2. Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany;
3. Core Facility Proteomics, ZEMFO, Rostock University Medical Center, Rostock, Germany;
4. Institute for Experimental Cancer Research, Medical Faculty, CAU, Kiel, and Department of Surgery, UKSH, Campus Kiel, Kiel, Germany;
5. Department of Neuropathology, University Hospital Charité, Berlin, Germany;
6. Department Life, Light and Matter of the Interdisciplinary Faculty at Rostock University, Rostock, Germany.
*Equally contributing first authors

✉ Corresponding author: Brigitte M. Pützer, MD, PhD, Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany. Tel: +49(0)3814945068, Fax: +49(0)3814945062, Email: brigitte.puetzeruni-rostock.de More

Abstract

Metastasis management remains a long-standing challenge. High abundance of E2F1 triggers tumor progression by developing protein-protein interactions (PPI) with coregulators that enhance its potential to activate a network of prometastatic transcriptional targets.

Methods: To identify E2F1-coregulators, we integrated high-throughput Co-immunoprecipitation (IP)/mass spectometry, GST-pull-down assays, and structure modeling. Potential inhibitors of PPI discovered were found by bioinformatics-based pharmacophore modeling, and transcriptome profiling was conducted to screen for coregulated downstream targets. Expression and target gene regulation was validated using qRT-PCR, immunoblotting, chromatin IP, and luciferase assays. Finally, the impact of the E2F1-coregulator complex and its inhibiting drug on metastasis was investigated in vitro in different cancer entities and two mouse metastasis models.

Results: We unveiled that E2F1 forms coactivator complexes with metastasis-associated protein 1 (MTA1) which, in turn, is directly upregulated by E2F1. The E2F1:MTA1 complex potentiates hyaluronan synthase 2 (HAS2) expression, increases hyaluronan production and promotes cell motility. Disruption of this prometastatic E2F1:MTA1 interaction reduces hyaluronan synthesis and infiltration of tumor-associated macrophages in the tumor microenvironment, thereby suppressing metastasis. We further demonstrate that E2F1:MTA1 assembly is abrogated by small-molecule, FDA-approved drugs. Treatment of E2F1/MTA1-positive, highly aggressive, circulating melanoma cells and orthotopic pancreatic tumors with argatroban prevents metastasis and cancer relapses in vivo through perturbation of the E2F1:MTA1/HAS2 axis.

Conclusion: Our results propose argatroban as an innovative, E2F-coregulator-based, antimetastatic drug. Cancer patients with the infaust E2F1/MTA1/HAS2 signature will likely benefit from drug repositioning.

Keywords: metastasis, E2F1-coregulator, MTA1, pharmacophore modeling, drug repositioning

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