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

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.
Mesh Terms:
Animals, Basic Helix-Loop-Helix Transcription Factors, Carcinoma, Renal Cell, Cell Line, Tumor, Disease Models, Animal, Feedback, Physiological, Gene Expression Profiling, Gene Expression Regulation, Genes, Tumor Suppressor, Heterografts, Humans, Interferon-Stimulated Gene Factor 3, gamma Subunit, Kidney Neoplasms, Mice, Nude, Neoplasm Transplantation, Von Hippel-Lindau Tumor Suppressor Protein
Date: Dec. 25, 2017
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