Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer

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.

Interferon Regulatory Factor 9 Promotes Lung Cancer Progression via Regulation of Versican

“…In a study of patients with clear cell RCC, patients with nuclei positive for IRF9 had a better prognosis than those with absent IRF9 expression. Similarly, to our findings in patients with lung cancer, the status of STAT2 did not influence survival in these patients [ 31 ]. In acute myeloid leukemia and prostate cancer, IRF9 acts as a tumor suppressor; in pancreatic diseases, it acts as an oncogene [ 29 , 41 , 42 ].…”

“…This result has been confirmed even in IFNα-resistant cells, such as in human glioblastoma multiforme [ 30 ]. In a renal cell adenocarcinoma study, IRF9 knockdown was shown to increase tumor formation in a xenograft model, whereas the overexpression of both IRF9 and STAT2 reduced tumor growth [ 31 ]. In lung adenocarcinoma (LUAD), IRF9 induced PD-L1 upregulation upon IFNβ stimulation, which indicates the presence of an immunosurveillance escape mechanism [ 32 ].…”

Functional interpretation of ovarian cancer in correlation with ISGF3 expression pattern

“…As previously reported in clear cell renal cell carcinoma, the loss of HIF2a, KDM5C or PBRM in VHL-/cells are able to downregulate the expression of ISGF3 [17]. Also, studies show that the loss of BAP1 or SETD2 reduces the expression level of ISGF3 which confirms its expression are interrelated to each other [17]. Correlating with ovarian cancer, the higher and lower expression of ISGF3 in initial and advanced stage of ovarian cancer may be also link with the related proteins like HIF2a, KDM5C, PBRM, BAP1 or SETD2.…”

“…The present investigation mainly focused on understanding ISGF3 expression pattern in different pathological stages of ovarian cancer. As previously reported in clear cell renal cell carcinoma, the loss of HIF2a, KDM5C or PBRM in VHL-/cells are able to downregulate the expression of ISGF3 [17]. Also, studies show that the loss of BAP1 or SETD2 reduces the expression level of ISGF3 which confirms its expression are interrelated to each other [17].…”

“…Previous studies with ISGF3 showed that its expression is associated with viral infection, DNA damage, and immunotherapies [16]. Recent investigation shows that ISGF3 is involved in tumor suppression of clear cell renal cell carcinoma (ccRCC) [17]. However, its role in ovarian cancer is not been explored so far.…”