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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
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.
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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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