Open AccessJunction plakoglobin regulates and destabilizes HIF2α to inhibit tumorigenesis of renal cell carcinoma
Author(s) -
Chen Ke,
Zeng Jin,
Sun Yi,
Ouyang Wei,
Yu Gan,
Zhou Hui,
Zhang Yangjun,
Yao Weimin,
Xiao Wei,
Hu Junhui,
Xing Jinchun,
Xiao Kefeng,
Wu Lily,
Chen Zhiqiang,
Ye Zhangqun,
Xu Hua
Publication year - 2021
Publication title -
cancer communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.119
H-Index - 53
ISSN - 2523-3548
DOI - 10.1002/cac2.12142
Subject(s) - clear cell renal cell carcinoma , chromatin immunoprecipitation , transactivation , gene knockdown , cancer research , carcinogenesis , hypoxia inducible factors , microbiology and biotechnology , biology , cell growth , chemistry , cell culture , transcription factor , cancer , gene expression , renal cell carcinoma , biochemistry , medicine , gene , genetics , promoter , pathology
Background 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. Methods 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. Results 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. Conclusion Taken together, these data support a role of JUP in modulating HIF2α signaling during ccRCC progression and identify JUP as a potential therapeutic target.