Therapeutic targeting of the PLK1-PRC1-axis triggers cell death in genomically silent childhood cancer

Nat Commun. 2021 Sep 16;12(1):5356. doi: 10.1038/s41467-021-25553-z.


Chromosomal instability (CIN) is a hallmark of cancer1. Yet, many childhood cancers, such as Ewing sarcoma (EwS), feature remarkably 'silent' genomes with minimal CIN2. Here, we show in the EwS model how uncoupling of mitosis and cytokinesis via targeting protein regulator of cytokinesis 1 (PRC1) or its activating polo-like kinase 1 (PLK1) can be employed to induce fatal genomic instability and tumor regression. We find that the EwS-specific oncogenic transcription factor EWSR1-FLI1 hijacks PRC1, which physiologically safeguards controlled cell division, through binding to a proximal enhancer-like GGAA-microsatellite, thereby promoting tumor growth and poor clinical outcome. Via integration of transcriptome-profiling and functional in vitro and in vivo experiments including CRISPR-mediated enhancer editing, we discover that high PRC1 expression creates a therapeutic vulnerability toward PLK1 inhibition that can repress even chemo-resistant EwS cells by triggering mitotic catastrophe.Collectively, our results exemplify how aberrant PRC1 activation by a dominant oncogene can confer malignancy but provide opportunities for targeted therapy, and identify PRC1 expression as an important determinant to predict the efficacy of PLK1 inhibitors being used in clinical trials.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Child
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Polo-Like Kinase 1
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • RNA Interference
  • RNAi Therapeutics / methods
  • Sarcoma, Ewing / genetics*
  • Sarcoma, Ewing / metabolism
  • Sarcoma, Ewing / therapy
  • Signal Transduction / genetics
  • Xenograft Model Antitumor Assays / methods


  • Cell Cycle Proteins
  • EWSR1-FLI1 fusion protein, human
  • Oncogene Proteins, Fusion
  • PRC1 protein, human
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases