BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma.
BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma.
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DOI：
10.1016/j.jbc.2021.101223
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Janes SM
中科院分区：
文献类型：
--
作者：
Ishii Y;Kolluri KK;Pennycuick A;Zhang X;Nigro E;Alrifai D;Borg E;Falzon M;Shah K;Kumar N;Janes SM
恶性胸膜间皮瘤（MPM）是一种罕见的，侵略性的，无法治愈的癌症产生的胸膜间皮瘤衬里，与几个可用的治疗方案。我们最近报道，核去泛素化酶BRCA 1相关蛋白1（BAP 1）的功能丧失，MPM中的常见事件，与肿瘤坏死因子相关凋亡诱导配体（TRAIL）介导的细胞凋亡的敏感性相关。作为一个潜在的潜在机制，在这里，我们报告BAP 1负调控TRAIL受体的表达：死亡受体4（DR4）和死亡受体5（DR5）。使用来自MPM患者的肿瘤样本的组织微阵列，我们发现BAP 1和TRAIL受体表达之间存在很强的负相关性。BAP 1敲除增加了DR4和DR5的表达，而BAP 1过表达则具有相反的效果。报告基因分析证实，野生型BAP1，但不是催化失活的BAP1突变体，减少启动子活动的DR4和DR5，这表明去泛素化酶活性是必需的基因表达的调节。免疫共沉淀研究表明BAP 1与转录因子Ying Yang 1（YY 1）直接结合，染色质免疫沉淀分析显示BAP 1和YY 1富集在DR4和DR5的启动子区域。YY1的敲除也增加了DR4和DR5的表达以及对TRAIL的敏感性。这些结果表明BAP 1和YY 1协同抑制TRAIL受体的转录。我们发现BAP 1直接调节外源性凋亡途径，这将为BAP 1在MPM和其他具有频繁BAP 1突变的癌症发展中的作用提供新的见解。
Malignant pleural mesothelioma (MPM) is a rare, aggressive, and incurable cancer arising from the mesothelial lining of the pleura, with few available treatment options. We recently reported that loss of function of the nuclear deubiquitinase BRCA1-associated protein 1 (BAP1), a frequent event in MPM, is associated with sensitivity to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–mediated apoptosis. As a potential underlying mechanism, here we report that BAP1 negatively regulates the expression of TRAIL receptors: death receptor 4 (DR4) and death receptor 5 (DR5). Using tissue microarrays of tumor samples from MPM patients, we found a strong inverse correlation between BAP1 and TRAIL receptor expression. BAP1 knockdown increased DR4 and DR5 expression, whereas overexpression of BAP1 had the opposite effect. Reporter assays confirmed wt-BAP1, but not catalytically inactive BAP1 mutant, reduced promoter activities of DR4 and DR5, suggesting deubiquitinase activity is required for the regulation of gene expression. Co-immunoprecipitation studies demonstrated direct binding of BAP1 to the transcription factor Ying Yang 1 (YY1), and chromatin immunoprecipitation assays revealed BAP1 and YY1 to be enriched in the promoter regions of DR4 and DR5. Knockdown of YY1 also increased DR4 and DR5 expression and sensitivity to TRAIL. These results suggest that BAP1 and YY1 cooperatively repress transcription of TRAIL receptors. Our finding that BAP1 directly regulates the extrinsic apoptotic pathway will provide new insights into the role of BAP1 in the development of MPM and other cancers with frequent BAP1 mutations.
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影响因子：
18.4
作者：
Deng D;Shah K
通讯作者：
Shah K
影响因子：
1.6
作者：
Andrici J;Goeppert B;Sioson L;Clarkson A;Renner M;Stenzinger A;Tayao M;Watson N;Farzin M;Toon CW;Smith RC;Mittal A;Samra JS;Hugh TJ;Chou A;Lawlor RT;Weichert W;Schirmacher P;Sperandio N;Ruzzenente A;Scarpa A;Gill AJ
通讯作者：
Gill AJ
影响因子：
11.5
作者：
Elias, Agnes;Siegelin, Markus D.;Mueller, Wolf
通讯作者：
Mueller, Wolf
影响因子：
3.8
作者：
Ewens KG;Lalonde E;Richards-Yutz J;Shields CL;Ganguly A
通讯作者：
Ganguly A
影响因子：
5.7
作者：
Baritaki, Stavroula;Huerta-Yepez, Sara;Bonavida, Benjamin
通讯作者：
Bonavida, Benjamin