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/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.
eLife. 2018 Oct 25 [Epub ahead of print]
Lili Liao, Zongzhi Z Liu, Lauren Langbein, Weijia Cai, Eun-Ah Cho, Jie Na, Xiaohua Niu, Wei Jiang, Zhijiu Zhong, Wesley L Cai, Geetha Jagannathan, Essel Dulaimi, Joseph R Testa, Robert G Uzzo, Yuxin Wang, George R Stark, Jianxin Sun, Stephen C Peiper, Yaomin Xu, Qin Yan, Haifeng Yang
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States., Department of Pathology, Yale University, New Haven, United States., Department of Health Sciences Research, Mayo Clinic, Rochester, United States., Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China., Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, United States., Fox Chase Cancer Center, Philadelphia, United States., Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States., Department of Medicine, Thomas Jefferson University, Philadelphia, United States., Department of Biostatistics, Vanderbilt University, Nashville, United States.