Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma
More than half of patients with malignant mesothelioma show alterations in the BAP1 tumor-suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome, which may create new vulnerabilities that remain largely unknown. Here, w...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9975229/ https://www.ncbi.nlm.nih.gov/pubmed/36657447 http://dx.doi.org/10.1016/j.xcrm.2022.100915 |
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author | Pandey, Gaurav Kumar Landman, Nick Neikes, Hannah K. Hulsman, Danielle Lieftink, Cor Beijersbergen, Roderick Kolluri, Krishna Kalyan Janes, Sam M. Vermeulen, Michiel Badhai, Jitendra van Lohuizen, Maarten |
author_facet | Pandey, Gaurav Kumar Landman, Nick Neikes, Hannah K. Hulsman, Danielle Lieftink, Cor Beijersbergen, Roderick Kolluri, Krishna Kalyan Janes, Sam M. Vermeulen, Michiel Badhai, Jitendra van Lohuizen, Maarten |
author_sort | Pandey, Gaurav Kumar |
collection | PubMed |
description | More than half of patients with malignant mesothelioma show alterations in the BAP1 tumor-suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome, which may create new vulnerabilities that remain largely unknown. Here, we performed a CRISPR-Cas9 kinome screen in mesothelioma cells that identified two kinases in the mevalonate/cholesterol biosynthesis pathway. Furthermore, our analysis of chromatin, expression, and genetic perturbation data in mesothelioma cells suggests a dependency on PR complex 2 (PRC2)-mediated silencing. Pharmacological inhibition of PRC2 elevates the expression of cholesterol biosynthesis genes only in BAP1-deficient mesothelioma, thereby sensitizing these cells to the combined targeting of PRC2 and the mevalonate pathway. Finally, by subjecting autochthonous Bap1-deficient mesothelioma mice or xenografts to mevalonate pathway inhibition (zoledronic acid) and PRC2 inhibition (tazemetostat), we demonstrate a potent anti-tumor effect, suggesting a targeted combination therapy for Bap1-deficient mesothelioma. |
format | Online Article Text |
id | pubmed-9975229 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-99752292023-03-02 Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma Pandey, Gaurav Kumar Landman, Nick Neikes, Hannah K. Hulsman, Danielle Lieftink, Cor Beijersbergen, Roderick Kolluri, Krishna Kalyan Janes, Sam M. Vermeulen, Michiel Badhai, Jitendra van Lohuizen, Maarten Cell Rep Med Article More than half of patients with malignant mesothelioma show alterations in the BAP1 tumor-suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome, which may create new vulnerabilities that remain largely unknown. Here, we performed a CRISPR-Cas9 kinome screen in mesothelioma cells that identified two kinases in the mevalonate/cholesterol biosynthesis pathway. Furthermore, our analysis of chromatin, expression, and genetic perturbation data in mesothelioma cells suggests a dependency on PR complex 2 (PRC2)-mediated silencing. Pharmacological inhibition of PRC2 elevates the expression of cholesterol biosynthesis genes only in BAP1-deficient mesothelioma, thereby sensitizing these cells to the combined targeting of PRC2 and the mevalonate pathway. Finally, by subjecting autochthonous Bap1-deficient mesothelioma mice or xenografts to mevalonate pathway inhibition (zoledronic acid) and PRC2 inhibition (tazemetostat), we demonstrate a potent anti-tumor effect, suggesting a targeted combination therapy for Bap1-deficient mesothelioma. Elsevier 2023-01-18 /pmc/articles/PMC9975229/ /pubmed/36657447 http://dx.doi.org/10.1016/j.xcrm.2022.100915 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Pandey, Gaurav Kumar Landman, Nick Neikes, Hannah K. Hulsman, Danielle Lieftink, Cor Beijersbergen, Roderick Kolluri, Krishna Kalyan Janes, Sam M. Vermeulen, Michiel Badhai, Jitendra van Lohuizen, Maarten Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma |
title | Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma |
title_full | Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma |
title_fullStr | Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma |
title_full_unstemmed | Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma |
title_short | Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma |
title_sort | genetic screens reveal new targetable vulnerabilities in bap1-deficient mesothelioma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9975229/ https://www.ncbi.nlm.nih.gov/pubmed/36657447 http://dx.doi.org/10.1016/j.xcrm.2022.100915 |
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