Junction plakoglobin regulates and destabilizes HIF2α to inhibit tumorigenesis of renal cell carcinoma.
Junction plakoglobin regulates and destabilizes HIF2α to inhibit tumorigenesis of renal cell carcinoma.
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连接斑珠蛋白调节和破坏 HIF2 α 的稳定性以抑制肾细胞癌的肿瘤发生
DOI：
10.1002/cac2.12142
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Xu H
中科院分区：
文献类型：
--
作者：
Chen K;Zeng J;Sun Y;Ouyang W;Yu G;Zhou H;Zhang Y;Yao W;Xiao W;Hu J;Xing J;Xiao K;Wu L;Chen Z;Ye Z;Xu H
缺氧诱导因子2α（HIF 2 α）激活增加是肾透明细胞癌（ccRCC）进展中的常见事件。然而，HIF 2 α在ccRCC中的功能和潜在机制尚未研究。我们进行了这项研究，以评估ccRCC中连接斑珠蛋白（JUP）和HIF 2 α之间的潜在联系。进行亲和纯化和质谱（AP-MS）筛选、谷胱甘肽硫转移酶（GST）下拉和免疫共沉淀（Co-IP）试验，以检测HIF 2 α的相互作用蛋白。采用定量PCR（qPCR）和Western blotting检测人ccRCC标本中JUP的表达。通过荧光素酶报告基因分析、染色质免疫沉淀（ChIP）、放线菌酮追踪分析和泛素化分析，探讨JUP对HIF 2 α活性的调节作用。进行细胞计数试剂盒-8（CCK-8）测定、集落形成测定、transwell测定和异种移植肿瘤测定，以研究JUP敲减或过表达对肾癌细胞致瘤性的影响。我们将JUP确定为一种新的HIF 2 α结合伴侣，并揭示了JUP在招募von Hippel-Lindau（VHL）和组蛋白脱乙酰酶1/2（HDAC 1/2）到HIF 2 α以调节其稳定性和反式激活方面的重要作用。JUP基因敲减可促进肾细胞癌的成瘤性，而过表达可抑制肾细胞癌的成瘤性。重要的是，在临床ccRCC样品中发现JUP的低表达，并且与缺氧评分增加和治疗结果差相关。总之，这些数据支持JUP在ccRCC进展期间调节HIF 2 α信号传导的作用，并将JUP确定为潜在的治疗靶点。我们提供了肿瘤抑制因子JUP与ccRCC细胞中HIF 2 α转录因子相互作用的机制。JUP下调可能触发HIF 2 α稳定性和反式活性的异常上调，这进一步影响ccRCC中的肿瘤发生。这些结果对肾细胞癌的诊断和治疗具有重要意义。
Increased hypoxia‐inducible factor 2α (HIF2α) activation is a common event in clear cell renal cell carcinoma (ccRCC) progression. However, the function and underlying mechanism of HIF2α in ccRCC remains uninvestigated. We conducted this study to access the potential link between junction plakoglobin (JUP) and HIF2α in ccRCC. Affinity purification and mass spectrometry (AP‐MS) screening, glutathione‐s‐transferase (GST) pull‐down and co‐immunoprecipitation (Co‐IP) assays were performed to detect the interacting proteins of HIF2α. Quantitative PCR (qPCR) and Western blotting were used to detect the expression of JUP in human ccRCC samples. Luciferase reporter assays, chromatin immunoprecipitation (ChIP), cycloheximide chase assays, and ubiquitination assays were conducted to explore the regulation of JUP on the activity of HIF2α. Cell Counting Kit‐8 (CCK‐8) assays, colony formation assays, transwell assays, and xenograft tumor assays were performed to investigate the effect of JUP knockdown or overexpression on the tumorigenicity of renal cancer cells. We identified JUP as a novel HIF2α‐binding partner and revealed an important role of JUP in recruiting von Hippel‐Lindau (VHL) and histone deacetylases 1/2 (HDAC1/2) to HIF2α to regulate its stability and transactivation. JUP knockdown promoted and overexpression suppressed the tumorigenicity of renal cell carcinoma in vitro and in vivo. Importantly, the low expression of JUP was found in clinical ccRCC samples and correlated with enhanced hypoxia scores and poor treatment outcomes. Taken together, these data support a role of JUP in modulating HIF2α signaling during ccRCC progression and identify JUP as a potential therapeutic target. We provide a mechanism by which the tumor suppressor JUP interact with the HIF2α transcription factor in ccRCC cells. JUP downregulation is likely to trigger the aberrant upregulation of HIF2α stability and transactivity, which further exerts effects on tumorigenesis in ccRCC. These results have important implications in both the diagnosis and treatment of RCC.
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通过plakoglobin的细胞亚分布和亲核剂的致癌潜力的调节。
影响因子：
6.2
作者：
Lam, L.;Aktary, Z.;Bishay, M.;Werkman, C.;Kuo, C-Y;Heacock, M.;Srivastava, N.;Mackey, J. R.;Pasdar, M.
通讯作者：
Pasdar, M.
影响因子：
11.4
作者：
Morgan, R. G.;Pearn, L.;Liddiard, K.;Pumford, S. L.;Burnett, A. K.;Tonks, A.;Darley, R. L.
通讯作者：
Darley, R. L.
影响因子：
--
作者：
Aktary Z;Alaee M;Pasdar M
通讯作者：
Pasdar M
影响因子：
64.5
作者：
Liu J;Lichtenberg T;Hoadley KA;Poisson LM;Lazar AJ;Cherniack AD;Kovatich AJ;Benz CC;Levine DA;Lee AV;Omberg L;Wolf DM;Shriver CD;Thorsson V;Cancer Genome Atlas Research Network;Hu H
通讯作者：
Hu H
影响因子：
30.8
作者：
Bhandari, Vinayak;Hoey, Christianne;Bristow, Robert G.
通讯作者：
Bristow, Robert G.