Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer

• Published in: eLife Vol. 7
• Main Authors: Liao, Lili, Liu, Zongzhi Z, Langbein, Lauren, Cai, Weijia, 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, Sun, Jianxin, Peiper, Stephen, Xu, Yaomin, Yan, Qin, Yang, Haifeng
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 25.10.2018; eLife Sciences Publications, Ltd
• Subjects: Animals; BAP1; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cancer Biology; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Chromosomes; Chromosomes and Gene Expression; Clear cell-type renal cell carcinoma; Disease Models, Animal; DNA methylation; Drug resistance; Enzymes; Feedback; Feedback, Physiological; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genes, Tumor Suppressor; Genomes; Heterografts; Humans; Hypoxia; Immunoglobulins; Interferon; Interferon-Stimulated Gene Factor 3, gamma Subunit - metabolism; ISGF3; KDM5C; Kidney cancer; Kidney Neoplasms - pathology; Laboratories; Mice, Nude; Mutation; Neoplasm Transplantation; PBRM1; Proteins; Tumor suppressor genes; Tumorigenesis; Tumors; VHL; VHL protein; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; Xenografts; United States > US; Tennessee; Pennsylvania; kidney cancer; ISGF3; KDM5C; PBRM1; chromosomes; cancer biology; VHL; human; BAP1; gene expression
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.37925

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.