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BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification
The nuclear deubiquitylase BRCA1-associated protein 1 (BAP1) is frequently inactivated in malignant pleural mesothelioma (MPM) and germline BAP1 mutation predisposes to cancers including MPM. To explore the influence on cell physiology and drug sensitivity, we sequentially edited a predisposition mu...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150242/ https://www.ncbi.nlm.nih.gov/pubmed/36669126 http://dx.doi.org/10.1158/1541-7786.MCR-22-0635 |
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author | Barnett, Sarah E. Kenyani, Jenna Tripari, Martina Butt, Zohra Grosman, Rudi Querques, Francesca Shaw, Liam Silva, Luisa C. Goate, Zoe Marciniak, Stefan J. Rassl, Doris M. Jackson, Richard Lian, Lu-Yun Szlosarek, Peter W. Sacco, Joseph J. Coulson, Judy M. |
author_facet | Barnett, Sarah E. Kenyani, Jenna Tripari, Martina Butt, Zohra Grosman, Rudi Querques, Francesca Shaw, Liam Silva, Luisa C. Goate, Zoe Marciniak, Stefan J. Rassl, Doris M. Jackson, Richard Lian, Lu-Yun Szlosarek, Peter W. Sacco, Joseph J. Coulson, Judy M. |
author_sort | Barnett, Sarah E. |
collection | PubMed |
description | The nuclear deubiquitylase BRCA1-associated protein 1 (BAP1) is frequently inactivated in malignant pleural mesothelioma (MPM) and germline BAP1 mutation predisposes to cancers including MPM. To explore the influence on cell physiology and drug sensitivity, we sequentially edited a predisposition mutation (w-) and a promoter trap (KO) into human mesothelial cells. BAP1(w-/KO) MeT5A cells express less BAP1 protein and phenocopy key aspects of BAP1 loss in MPM. Stable isotope labeling with amino acids in cell culture–mass spectrometry revealed evidence of metabolic adaptation, with concomitant alteration of cellular metabolites. In MeT5A, BAP1 deficiency reduces glycolytic enzyme levels but increases enzymes involved in the tricarboxylic acid cycle and anaplerotic pathways. Notably both argininosuccinate synthase 1 (ASS1), essential for cellular synthesis of arginine, and its substrate aspartate, are elevated in BAP1(w-/KO) MeT5A cells. Likewise, ASS1 expression is higher in BAP1-altered MPM cell lines, and inversely correlates with BAP1 in The Cancer Genome Atlas MESO dataset. Elevated ASS1 is also evident by IHC staining in epithelioid MPM lacking nuclear BAP1 expression, with improved survival among patients with BAP1-negative/ASS1-expressing tumors. Alterations in arginine metabolism may sensitize cells to metabolic drugs and we find that BAP1-negative/ASS1-expressing MPM cell lines are more sensitive to ASS1 inhibition, although not to inhibition of purine synthesis by mizoribine. Importantly, BAP1(w-/KO) MeT5A become desensitized to arginine deprivation by pegylated arginine deiminase (ADI-PEG20), phenocopying BAP1-negative/ASS1-expressing MPM cell lines. IMPLICATIONS: Our data reveal an interrelationship between BAP1 and arginine metabolism, providing a potential means of identifying patients with epithelioid MPM likely to benefit from ADI-PEG20. |
format | Online Article Text |
id | pubmed-10150242 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-101502422023-05-02 BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification Barnett, Sarah E. Kenyani, Jenna Tripari, Martina Butt, Zohra Grosman, Rudi Querques, Francesca Shaw, Liam Silva, Luisa C. Goate, Zoe Marciniak, Stefan J. Rassl, Doris M. Jackson, Richard Lian, Lu-Yun Szlosarek, Peter W. Sacco, Joseph J. Coulson, Judy M. Mol Cancer Res Cancer Genes and Networks The nuclear deubiquitylase BRCA1-associated protein 1 (BAP1) is frequently inactivated in malignant pleural mesothelioma (MPM) and germline BAP1 mutation predisposes to cancers including MPM. To explore the influence on cell physiology and drug sensitivity, we sequentially edited a predisposition mutation (w-) and a promoter trap (KO) into human mesothelial cells. BAP1(w-/KO) MeT5A cells express less BAP1 protein and phenocopy key aspects of BAP1 loss in MPM. Stable isotope labeling with amino acids in cell culture–mass spectrometry revealed evidence of metabolic adaptation, with concomitant alteration of cellular metabolites. In MeT5A, BAP1 deficiency reduces glycolytic enzyme levels but increases enzymes involved in the tricarboxylic acid cycle and anaplerotic pathways. Notably both argininosuccinate synthase 1 (ASS1), essential for cellular synthesis of arginine, and its substrate aspartate, are elevated in BAP1(w-/KO) MeT5A cells. Likewise, ASS1 expression is higher in BAP1-altered MPM cell lines, and inversely correlates with BAP1 in The Cancer Genome Atlas MESO dataset. Elevated ASS1 is also evident by IHC staining in epithelioid MPM lacking nuclear BAP1 expression, with improved survival among patients with BAP1-negative/ASS1-expressing tumors. Alterations in arginine metabolism may sensitize cells to metabolic drugs and we find that BAP1-negative/ASS1-expressing MPM cell lines are more sensitive to ASS1 inhibition, although not to inhibition of purine synthesis by mizoribine. Importantly, BAP1(w-/KO) MeT5A become desensitized to arginine deprivation by pegylated arginine deiminase (ADI-PEG20), phenocopying BAP1-negative/ASS1-expressing MPM cell lines. IMPLICATIONS: Our data reveal an interrelationship between BAP1 and arginine metabolism, providing a potential means of identifying patients with epithelioid MPM likely to benefit from ADI-PEG20. American Association for Cancer Research 2023-05-01 2023-01-20 /pmc/articles/PMC10150242/ /pubmed/36669126 http://dx.doi.org/10.1158/1541-7786.MCR-22-0635 Text en ©2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license. |
spellingShingle | Cancer Genes and Networks Barnett, Sarah E. Kenyani, Jenna Tripari, Martina Butt, Zohra Grosman, Rudi Querques, Francesca Shaw, Liam Silva, Luisa C. Goate, Zoe Marciniak, Stefan J. Rassl, Doris M. Jackson, Richard Lian, Lu-Yun Szlosarek, Peter W. Sacco, Joseph J. Coulson, Judy M. BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification |
title | BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification |
title_full | BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification |
title_fullStr | BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification |
title_full_unstemmed | BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification |
title_short | BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification |
title_sort | bap1 loss is associated with higher ass1 expression in epithelioid mesothelioma: implications for therapeutic stratification |
topic | Cancer Genes and Networks |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150242/ https://www.ncbi.nlm.nih.gov/pubmed/36669126 http://dx.doi.org/10.1158/1541-7786.MCR-22-0635 |
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