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Therapeutic targeting of the PLK1-PRC1-axis triggers cell death in genomically silent childhood cancer
- Source :
- Nature Communications, Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021), Repisalud, Instituto de Salud Carlos III (ISCIII)
- Publication Year :
- 2021
- Publisher :
- Nature Publishing Group UK, 2021.
-
Abstract
- 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.<br />In this study, the authors show that that oncogenic hijacking of PRC1 sensitizes genomically stable Ewing sarcoma cells for PLK1 inhibition alone or in synergy with a microtubule-destabilizing drug via induction of cytokinesis defects, rendering PRC1 a promising, broadly applicable predictive biomarker
- Subjects :
- Genome instability
Oncogene Proteins, Fusion
medicine.medical_treatment
Science
Medizin
General Physics and Astronomy
Apoptosis
Cell Cycle Proteins
macromolecular substances
Kaplan-Meier Estimate
Mice, SCID
Sarcoma, Ewing
Biology
Protein Serine-Threonine Kinases
Predictive markers
PLK1
General Biochemistry, Genetics and Molecular Biology
Article
Targeted therapy
Tumour biomarkers
Paediatric cancer
Mice, Inbred NOD
Chromosome instability
Cell Line, Tumor
Proto-Oncogene Proteins
medicine
Bone cancer
Animals
Humans
Child
Transcription factor
Mitosis
Mice, Knockout
Multidisciplinary
Gene Expression Profiling
General Chemistry
Xenograft Model Antitumor Assays
Gene Expression Regulation, Neoplastic
HEK293 Cells
RNAi Therapeutics
Cancer research
RNA Interference
PRC1
Cytokinesis
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....909cbd8d20fa8876533f68b48a3b2e14