Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Apoptosis / genetics
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CRISPR-Cas Systems / genetics
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Carcinogenesis / drug effects
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Carcinogenesis / genetics*
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Cell Cycle Proteins / genetics*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Drug Resistance, Neoplasm / genetics*
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Gene Expression Regulation, Neoplastic
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Gene Knockdown Techniques
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Gene Knockout Techniques
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Humans
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M Phase Cell Cycle Checkpoints / drug effects
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Mutation
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Neoplasms / drug therapy
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Neoplasms / genetics*
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Neoplasms / pathology
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Polycomb Repressive Complex 1 / antagonists & inhibitors
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Polycomb Repressive Complex 1 / genetics
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Polycomb Repressive Complex 1 / metabolism*
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RNA, Small Interfering / metabolism
Substances
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Antineoplastic Agents
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BMI1 protein, human
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Cell Cycle Proteins
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NUMA1 protein, human
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RNA, Small Interfering
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Polycomb Repressive Complex 1
Grants and funding
MVL and SGB: Netherlands Institute of regenerative medicine (NIRM) 58473. MVL and SGB: Netherlands organization for scientific research (NWO) 823.02.007. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.