Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer
| Autor: | Qin Yan, Stephen C. Peiper, Zhijiu Zhong, Wesley L. Cai, Lili Liao, Jie Na, Essel Dulaimi, Yaomin Xu, George R. Stark, Weijia Cai, Robert G. Uzzo, Geetha Jagannathan, Wei Jiang, Joseph R. Testa, Haifeng Yang, Xiaohua Niu, Yuxin Wang, Jianxin Sun, Zongzhi Liu, Lauren Langbein, Eun-Ah Cho |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
QH301-705.5 Science General Biochemistry Genetics and Molecular Biology PBRM1 law.invention 03 medical and health sciences law Interferon VHL medicine Humans BAP1 Biology (General) Carcinoma Renal Cell Transcription factor Cancer Biology Cell Proliferation General Immunology and Microbiology Chemistry General Neuroscience kidney cancer General Medicine Chromosomes and Gene Expression medicine.disease Kidney Neoplasms Clear cell renal cell carcinoma 030104 developmental biology KDM5C Interferon-Stimulated Gene Factor 3 Cancer research ISGF3 Medicine Suppressor Clear cell Research Article Human medicine.drug |
| Zdroj: | eLife, Vol 7 (2018) eLife |
| ISSN: | 2050-084X |
| Popis: | WhereasVHLinactivation is a primary event in clear cell renal cell carcinoma (ccRCC), the precise mechanism(s) of how this interacts with the secondary mutations in tumor suppressor genes, includingPBRM1,KDM5C/JARID1C,SETD2, and/orBAP1, remains unclear. Gene expression analyses reveal that VHL, PBRM1, or KDM5C share a common regulation of interferon response expression signature. Loss of HIF2α, PBRM1, or KDM5C inVHL-/-cells reduces the expression of interferon stimulated gene factor 3 (ISGF3), a transcription factor that regulates the interferon signature. Moreover, loss of SETD2 or BAP1 also reduces the ISGF3 level. Finally, ISGF3 is strongly tumor-suppressive in a xenograft model as its loss significantly enhances tumor growth. Conversely, reactivation of ISGF3 retards tumor growth by PBRM1-deficient ccRCC cells. Thus afterVHLinactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC. |
| Databáze: | OpenAIRE |
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