Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer
Abstract
WhereasVHLinactivation 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, includingPBRM1,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 HIF2α, PBRM1, or KDM5C inVHL-/-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 afterVHLinactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 25, 2018
- Source ID
- 10.7554/elife.37925
Entities
People
- Essel Dulaimi
- Eun-ah Cho
- Geetha Jagannathan
- George R Stark
- Haifeng Yang
- Jianxin Sun
- Jie Na
- Joseph R. Testa
- Lauren Langbein
- Lili Liao
- Qin Yan
- Robert G. Uzzo
- Stephen Peiper
- Wei Jiang
- Weijia Cai
- Wesley L. Cai
- Xiaohua Niu
- Yaomin Xu
- Yuxin Wang
- Zhijiu Zhong
- Zongzhi Z. Liu
Organizations
- Cleveland Clinic
- Fox Chase Cancer Center
- Mayo Clinic
- National Cancer Institute
- Thomas Jefferson University
- United States Department of Defense
- Vanderbilt University
- Yale University