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

Theranostics. 2019 Feb 20;9(5):1490-1509. doi: 10.7150/thno.29546. eCollection 2019.


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: E2F1-coregulator; MTA1; drug repositioning; metastasis; pharmacophore modeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / isolation & purification
  • Antineoplastic Agents / pharmacology
  • Arginine / analogs & derivatives
  • Cell Line
  • Drug Evaluation, Preclinical / methods*
  • Drug Repositioning / methods*
  • E2F1 Transcription Factor / metabolism*
  • Gene Regulatory Networks / drug effects
  • Humans
  • Mice
  • Models, Theoretical
  • Neoplasm Metastasis / drug therapy*
  • Neoplasm Metastasis / prevention & control*
  • Neoplasms / drug therapy*
  • Pipecolic Acids / isolation & purification
  • Pipecolic Acids / pharmacology
  • Platelet Aggregation Inhibitors / isolation & purification
  • Platelet Aggregation Inhibitors / pharmacology
  • Protein Interaction Maps / drug effects*
  • Sulfonamides


  • Antineoplastic Agents
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Pipecolic Acids
  • Platelet Aggregation Inhibitors
  • Sulfonamides
  • Arginine
  • argatroban