دورية أكاديمية
A genome-wide enrichment screen identifies NUMA1-loss as a resistance mechanism against mitotic cell-death induced by BMI1 inhibition.
العنوان: | A genome-wide enrichment screen identifies NUMA1-loss as a resistance mechanism against mitotic cell-death induced by BMI1 inhibition. |
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المؤلفون: | Gisler S; Division of Molecular Genetics, Oncode and The Netherlands Cancer Institute, Amsterdam, The Netherlands., Maia ARR; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Chandrasekaran G; Division of Molecular Genetics, Oncode and The Netherlands Cancer Institute, Amsterdam, The Netherlands., Kopparam J; Division of Molecular Genetics, Oncode and The Netherlands Cancer Institute, Amsterdam, The Netherlands., van Lohuizen M; Division of Molecular Genetics, Oncode and The Netherlands Cancer Institute, Amsterdam, The Netherlands. |
المصدر: | PloS one [PLoS One] 2020 Apr 28; Vol. 15 (4), pp. e0227592. Date of Electronic Publication: 2020 Apr 28 (Print Publication: 2020). |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: San Francisco, CA : Public Library of Science |
مواضيع طبية MeSH: | Antineoplastic Agents/*pharmacology , Carcinogenesis/*genetics , Cell Cycle Proteins/*genetics , Drug Resistance, Neoplasm/*genetics , Neoplasms/*genetics , Polycomb Repressive Complex 1/*metabolism, Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Apoptosis/genetics ; CRISPR-Cas Systems/genetics ; Carcinogenesis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Proliferation/genetics ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Gene Knockout Techniques ; Humans ; M Phase Cell Cycle Checkpoints/drug effects ; Mutation ; Neoplasms/drug therapy ; Neoplasms/pathology ; Polycomb Repressive Complex 1/antagonists & inhibitors ; Polycomb Repressive Complex 1/genetics ; RNA, Small Interfering/metabolism |
مستخلص: | 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. Competing Interests: The authors have declared that no competing interests exist. |
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المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (BMI1 protein, human) 0 (Cell Cycle Proteins) 0 (NUMA1 protein, human) 0 (RNA, Small Interfering) EC 2.3.2.27 (Polycomb Repressive Complex 1) |
تواريخ الأحداث: | Date Created: 20200429 Date Completed: 20200706 Latest Revision: 20231113 |
رمز التحديث: | 20231113 |
مُعرف محوري في PubMed: | PMC7188281 |
DOI: | 10.1371/journal.pone.0227592 |
PMID: | 32343689 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1932-6203 |
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DOI: | 10.1371/journal.pone.0227592 |