Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer
Authors: Robert G Uzzo
Lili Liao
George R Stark
Zongzhi Z Liu
Weijia Cai
Joseph R Testa
Eun-Ah Cho
Wei Jiang
Lauren Langbein
Zhijiu Zhong
Qin Yan
Wesley L Cai
Jianxin Sun
Xiaohua Niu
Stephen Peiper
Essel Dulaimi
Haifeng Yang
Jie Na
Yuxin Wang
Geetha Jagannathan
Yaomin Xu
Journal: eLife (2018)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: BAP1; ISGF3; KDM5C; PBRM1; VHL
Affiliations: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United States., Department of Pathology, Yale University, Connecticut, United States., Fox Chase Cancer Center, Pennsylvania, United States., Department of Health Sciences Research, Mayo Clinic, Minnesota, United States., Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China., Sidney Kimmel Cancer Center, Thomas Jefferson University, Pennsylvania, United States., Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Ohio, United States., Department of Medicine, Thomas Jefferson University, Pennsylvania, United States., Department of Biostatistics, Vanderbilt University Medical Center, Tennessee, United States., Department of Biomedical Informatics, Vanderbilt University Medical Center, Tennessee, United States.

Abstract:  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. 

Retracted: No

PubPeer comments:
 Figure 5 - figure supplement 1 appears to have a repeated band after dimensions are adjusted. https: doi.org 10.7554 eLife.37925.007 The the authors please check? *** False color ![file] *** Original ![file] , 
 #1 Dear Actinopolyspora: We checked the original data and found out that we made a mistake. When the figure was prepared, the western blot bands were copied from the original files and pasted onto a new file. It is likely that during this process the anti-HA blot from Ren-01 was distorted, and it led to the mistaken belief that it was the anti-HA blot from Caki-1. An earlier powerpoint file from the person who performed the experiment showed all the right bands. The inspection of all the original blots also confirmed our mistake. We regret making this avoidable mistake and have worked with the journal to have it corrected, which is posted below. Thank you for pointing this out. Corrected eLife paper https: elifesciences.org articles 37925 Correction Notice https: elifesciences.org articles 69256 ,