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Liao L , Liu ZZ , Langbein L , Cai W , Cho EA , Na J , Niu X , Jiang W , Zhong Z , Cai WL , Jagannathan G , Dulaimi E , Testa JR , Uzzo RG , Wang Y , Stark GR , Sun J , Peiper S , Xu Y , Yan Q , Yang H
Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer
Elife. 2018 Oct 25;7
PMID: 30355451 PMCID: PMC6234029 URL: https://www.ncbi.nlm.nih.gov/pubmed/30355451
AbstractWhereas VHL inactivation 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, including PBRM1, 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 HIF2a, PBRM1, or KDM5C in VHL-/-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 after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC.
Notes2050-084x Liao, Lili Liu, Zongzhi Z Langbein, Lauren ORCID: http://orcid.org/0000-0002-3007-5287 Cai, Weijia Cho, Eun-Ah Na, Jie Niu, Xiaohua Jiang, Wei Zhong, Zhijiu Cai, Wesley L Jagannathan, Geetha Dulaimi, Essel Testa, Joseph R Uzzo, Robert G Wang, Yuxin Stark, George R Sun, Jianxin Peiper, Stephen C Xu, Yaomin Yan, Qin ORCID: http://orcid.org/0000-0003-4077-453X Yang, Haifeng ORCID: http://orcid.org/0000-0002-0892-9055 R01 CA155015/National Cancer Institute P30CA056036/National Cancer Institute W81XWH-16-1-0326/Department of Defence Journal Article England Elife. 2018 Oct 25;7. pii: 37925. doi: 10.7554/eLife.37925.