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/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.
Microarray data have been deposited inn GEO under the accession code GSE108229.
Microarray analysis of gene expression after suppression of PBRM1 or KDM5C in 786-O VHL+/+ or VHL-/- cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE108229).
Article and author information
National Cancer Institute (R01 CA155015)
- Haifeng Yang
National Cancer Institute (P30CA056036)
- Haifeng Yang
Department of Defence (W81XWH-16-1-0326)
- Qin Yan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animal experiments were conducted in accordance with protocol 01462-935A approved by the IACUC of Thomas Jefferson University and protocol 2015-11286 approved by the IACUC of Yale University.
- Irwin Davidson, Institut de Génétique et de Biologie Moléculaire et Cellulaire, France
- Received: April 27, 2018
- Accepted: October 22, 2018
- Accepted Manuscript published: October 25, 2018 (version 1)
- Version of Record published: November 13, 2018 (version 2)
- Version of Record updated: April 21, 2021 (version 3)
© 2018, Liao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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