Citations 1
Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer
Liao, Lili, Langbein, Lauren , Cho, Eun-Ah , Niu, Xiaohua , Jiang, Wei , Zhong, Zhijiu , Cai, Wesley L. , Jagannathan, Geetha , Dulaimi, Essel, Testa, Joseph R. , Uzzo, Robert G. , Wang, Yuxin , Stark, George R. , Peiper, Stephen C., Yan, Qin , Yang, Haifeng , Langbein, Lauren , Na, Jie , Xu, Yaomin , Yan, Qin , Yang, Haifeng , Liu, Zongzhi Z. , Cai, Weijia , Na, Jie, Sun, Jianxin
eLife | October 25, 2018 | Volume: 7 | Issue: No issue available | Pages: No page available
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.