The majority of clear cell renal cell carcinomas (ccRCC) harbour loss-of-function mutations in VHL that lead to increased levels of HIF2α, a pivotal oncogenic transcription factor. HIF2α also functionally interacts with secondary tumour suppressor genes such as KDM5C and PBRM1, which are often mutated in ccRCC. Now, Yaomin Xu, Qin Yan, Haifeng Yang and colleagues report that HIF2α and several chromatin regulators that are disabled in ccRCC enhance the expression of the transcription factor ISGF3, a regulator of the type I interferon response.
“We were intrigued by the mutations of multiple chromatin regulators such as PBRM1, KDM5C, SETD2 and BAP1 in ccRCC,” explains Xu. The researchers show that in VHL–/– cell lines, loss of any of these chromatin regulators reduced the levels of the ISGF3 components IRF9 and STAT2, as well as the expression of ISGF3 target genes.
In a xenograft model, loss of any of the three ISGF3 components — IRF9, STAT1 or STAT2 — resulted in a significant increase in tumour size. Tumours in which IRF9 was knocked down were mainly composed of cancer cells, whereas immune cells were more abundant in control tumours. No differences were observed in cancer cell proliferation or apoptosis. These results suggest that ISGF3-mediated tumour suppression might be linked to immune modulation. Consistent with a protective role of ISGF3, loss of nuclear IRF9 staining in human ccRCC tissue samples was associated with reduced patient survival.
“Mutations in VHL activate tumour suppressive ISGF3 via HIF2α but mutations in any of the secondary tumour suppressors disable this negative feedback loop. The fact that the secondary tumour suppressors share the regulation of ISGF3 suggests that this is a central tumour suppressive pathway in ccRCC,” concludes Yang. “Boosting ISGF3, either alone or in combination with other drugs, might be beneficial in patients with RCC,” adds Yan.
Liao, L. et al. Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer. eLife https://doi.org/10.7554/eLife.37925 (2018)
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Wang, M. A central anti-oncogenic pathway in ccRCC. Nat Rev Nephrol 15, 2 (2019). https://doi.org/10.1038/s41581-018-0083-6