PloS one, 2020-04, Vol.15 (4), p.e0227592
2020
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- Autor(en) / Beteiligte
- Titel
- A genome-wide enrichment screen identifies NUMA1-loss as a resistance mechanism against mitotic cell-death induced by BMI1 inhibition
- Ist Teil von
- PloS one, 2020-04, Vol.15 (4), p.e0227592
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2020
- Quelle
- EZB Electronic Journals Library
- Beschreibungen/Notizen
- BMI1 is a core protein of the polycomb repressive complex 1 (PRC1) that is overexpressed in several cancer types, making it a promising target for cancer therapies. However, the underlying mechanisms and interactions associated with BMI1-induced tumorigenesis are often context-dependent and complex. Here, we performed a drug resistance screen on mutagenized human haploid HAP1 cells treated with BMI1 inhibitor PTC-318 to find new genetic and mechanistic features associated with BMI1-dependent cancer cell proliferation. Our screen identified NUMA1-mutations as the most significant inducer of PTC-318 cell death resistance. Independent validations on NUMA1-proficient HAP1 and non-small cell lung cancer cell lines exposed to BMI1 inhibition by PTC-318 or BMI1 knockdown resulted in cell death following mitotic arrest. Interestingly, cells with CRISPR-Cas9 derived NUMA1 knockout also showed a mitotic arrest phenotype following BMI1 inhibition but, contrary to cells with wildtype NUMA1, these cells were resistant to BMI1-dependent cell death. The current study brings new insights to BMI1 inhibition-induced mitotic lethality in cancer cells and presents a previously unknown role of NUMA1 in this process.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0227592Titel-ID: cdi_plos_journals_2395614607
- Format
- –
- Schlagworte
- Antibiotics, Apoptosis, Biochemistry, Biology and Life Sciences, Cancer, Cancer cells, Cancer research, Cancer therapies, Cancer treatment, Cell death, Cell growth, Cell proliferation, Core protein, CRISPR, Cytotoxicity, Drug resistance, Gene expression, Genetic aspects, Genetics, Genomes, Genomics, Health aspects, Lethality, Lung cancer, Lung diseases, Medicine and Health Sciences, Mortality, Mutagenesis, Mutation, Non-small cell lung cancer, Non-small cell lung carcinoma, Phenotypes, Polycomb group proteins, Protein expression, Proteins, Research and Analysis Methods, Small cell lung cancer, Small cell lung carcinoma, Stem cells, Tumor cell lines, Tumorigenesis, Tumors