Document Type
Article
Publication Date
10-25-2018
Abstract
Whereas 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/or BAP1, 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 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. © 2018, Liao et al.
Recommended Citation
Liao, Lili; Liu, Zongzhi Z.; Langbein, Lauren; 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; and Yang, Haifeng, "Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer." (2018). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 262.
https://jdc.jefferson.edu/pacbfp/262
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
30355451
Language
English
Comments
This article has been peer reviewed. It is the author’s final published version in eLife, Volume 7, October 2018, Article number e37925.
The published version is available at https://doi.org/10.7554/eLife.37925. Copyright © Liao et al.