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Phenotypic Screen Identifies JAK2 as a Major Regulator of FAT10 Expression.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-12-10 , DOI: 10.1021/acschembio.9b00667 Nava Reznik 1, 2 , Noga Kozer 3 , Avital Eisenberg-Lerner 1 , Haim Barr 3 , Yifat Merbl 1 , Nir London 2
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-12-10 , DOI: 10.1021/acschembio.9b00667 Nava Reznik 1, 2 , Noga Kozer 3 , Avital Eisenberg-Lerner 1 , Haim Barr 3 , Yifat Merbl 1 , Nir London 2
Affiliation
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FAT10 is a ubiquitin-like protein suggested to target proteins for proteasomal degradation. It is highly upregulated upon pro-inflammatory cytokines, namely, TNFα, IFNγ, and IL6, and was found to be highly expressed in various epithelial cancers. Evidence suggests that FAT10 is involved in cancer development and may have a pro-tumorigenic role. However, its biological role is still unclear, as well as its biochemical and cellular regulation. To identify pathways underlying FAT10 expression in the context of pro-inflammatory stimulation, which characterizes the cancerous environment, we implemented a phenotypic transcriptional reporter screen with a library of annotated compounds. We identified AZ960, a potent JAK2 inhibitor, which significantly downregulates FAT10 under pro-inflammatory cytokines induction, in an NFκB-independent manner. We validated JAK2 as a major regulator of FAT10 expression via knockdown, and we suggest that the transcriptional effects are mediated through pSTAT1/3/5. Overall, we have elucidated a pathway regulating FAT10 transcription and discovered a tool compound to chemically downregulate FAT10 expression, and to further study its biology.
中文翻译：
表型筛选确定JAK2是FAT10表达的主要调节因子。
FAT10是一种泛素样蛋白，建议将其靶向用于蛋白酶体降解。它在促炎细胞因子TNFα，IFNγ和IL6上高度上调，并且发现在各种上皮癌中高度表达。有证据表明，FAT10参与了癌症的发展，可能具有促肿瘤作用。但是，其生物学作用以及其生化和细胞调节尚不清楚。为了在促炎刺激的背景下（特征在于癌性环境）确定FAT10表达的基础途径，我们实施了带注释化合物文库的表型转录报告基因筛选。我们鉴定了一种有效的JAK2抑制剂AZ960，它以非NFκB依赖性的方式在促炎性细胞因子诱导下显着下调FAT10。我们通过敲除验证了JAK2是FAT10表达的主要调节因子，并且我们认为转录作用是通过pSTAT1 / 3/5介导的。总体而言，我们阐明了调节FAT10转录的途径，并发现了一种化学上调FAT10表达并进一步研究其生物学的工具化合物。
更新日期：2019-12-11
中文翻译：
表型筛选确定JAK2是FAT10表达的主要调节因子。
FAT10是一种泛素样蛋白，建议将其靶向用于蛋白酶体降解。它在促炎细胞因子TNFα，IFNγ和IL6上高度上调，并且发现在各种上皮癌中高度表达。有证据表明，FAT10参与了癌症的发展，可能具有促肿瘤作用。但是，其生物学作用以及其生化和细胞调节尚不清楚。为了在促炎刺激的背景下（特征在于癌性环境）确定FAT10表达的基础途径，我们实施了带注释化合物文库的表型转录报告基因筛选。我们鉴定了一种有效的JAK2抑制剂AZ960，它以非NFκB依赖性的方式在促炎性细胞因子诱导下显着下调FAT10。我们通过敲除验证了JAK2是FAT10表达的主要调节因子，并且我们认为转录作用是通过pSTAT1 / 3/5介导的。总体而言，我们阐明了调节FAT10转录的途径，并发现了一种化学上调FAT10表达并进一步研究其生物学的工具化合物。
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