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 CitationLiao, 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.
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