BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification.
BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification.
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DOI：
10.1158/1541-7786.mcr-22-0635
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发表时间：
2023-05-01
影响因子：
5.2
通讯作者：
Coulson, Judy M.
中科院分区：
文献类型：
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作者：
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.
核脱泛素酶BRCA1相关蛋白1(BAP1)在恶性胸膜间皮瘤(MPM)中经常失活，胚系BAP1突变易发生包括MPM在内的肿瘤。为了探索对细胞生理和药物敏感性的影响，我们先后编辑了易感突变(w-)和启动子TRAP(KO)到人间皮细胞中。BAP1w/KO MeT5A细胞表达较少的BAP1蛋白和MPM中BAP1缺失的关键表型。细胞培养中氨基酸的稳定同位素标记-质谱仪显示了代谢适应的证据，并伴随着细胞代谢产物的变化。在MeT5A中，BAP1缺乏降低了糖酵解酶的水平，但增加了参与三羧酸循环和停滞途径的酶。值得注意的是，精氨酸琥珀酸合成酶1(ASS1)是细胞合成精氨酸所必需的，其底物天冬氨酸在BAP1w/KO MeT5A细胞中都升高。同样，ASS1在BAP1改变的MPM细胞系中的表达更高，并且在癌症基因组图谱中与BAP1负相关。在缺乏核BAP1表达的上皮样MPM中，通过IHC染色，ASS1的升高也是明显的，在BAP1阴性/ASS1表达的肿瘤患者中，提高了存活率。精氨酸代谢的改变可能使细胞对代谢性药物敏感，我们发现BAP1阴性/ASS1表达的MPM细胞系对ASS1抑制更敏感，但对咪唑立宾抑制嘌呤合成不敏感。重要的是，BAP1w/KO MeT5A通过聚乙二醇化精氨酸脱亚胺酶(ADI-PEG20)，与BAP1阴性/ASS1表达的MPM细胞株发生表型复制，从而对精氨酸缺乏失去敏感性。我们的数据揭示了BAP1和精氨酸代谢之间的相互关系，为识别可能受益于ADI-PEG20的上皮样MPM患者提供了一种潜在的手段。
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. BAP1w-/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 BAP1w-/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, BAP1w-/KO MeT5A become desensitized to arginine deprivation by pegylated arginine deiminase (ADI-PEG20), phenocopying BAP1-negative/ASS1-expressing MPM cell lines. 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.