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).
- Haifeng Yang
- Haifeng Yang
- 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
© 2018, Liao et al.
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