Theranostics 2019; 9(5):1490-1509. doi:10.7150/thno.29546
Drug Repositioning Inferred from E2F1-Coregulator Interactions Studies for the Prevention and Treatment of Metastatic Cancers
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
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
Goody D, Gupta SK, Engelmann D, Spitschak A, Marquardt S, Mikkat S, Meier C, Hauser C, Gundlach JP, Egberts JH, Martin H, Schumacher T, Trauzold A, Wolkenhauer O, Logotheti S, Pützer BM. Drug Repositioning Inferred from E2F1-Coregulator Interactions Studies for the Prevention and Treatment of Metastatic Cancers. Theranostics 2019; 9(5):1490-1509. doi:10.7150/thno.29546. Available from http://www.thno.org/v09p1490.htm