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.
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.