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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Clear cell renal cell carcinoma (ccRCC) is strongly linked to VHL gene inactivation.
• The interplay between VHL inactivation and secondary mutations in tumor suppressors (PBRM1, KDM5C, SETD2, BAP1) is not fully understood.

Purpose of the Study:

• To elucidate the functional relationship between VHL, secondary tumor suppressors, and the interferon response pathway in ccRCC.
• To investigate the role of interferon stimulated gene factor 3 (ISGF3) in ccRCC tumor suppression.

Main Methods:

• Gene expression analysis was performed on ccRCC samples and cell lines.
• Functional assays involved gene knockout (VHL, PBRM1, KDM5C, SETD2, BAP1) and assessment of ISGF3 levels.
• Tumor growth was evaluated in a xenograft model with manipulation of ISGF3 expression.

Main Results:

• VHL, PBRM1, and KDM5C were found to commonly regulate the interferon response signature.
• Loss of VHL, PBRM1, KDM5C, SETD2, or BAP1 led to reduced ISGF3 expression.
• ISGF3 demonstrated significant tumor-suppressive activity, with its loss enhancing tumor growth in vivo.

Conclusions:

• VHL inactivation initiates ccRCC, and subsequent loss of secondary tumor suppressors reverses HIF-induced ISGF3 expression.
• This VHL-HIF-ISGF3 axis represents a critical negative feedback mechanism in ccRCC pathogenesis.
• Restoring ISGF3 function may offer a therapeutic strategy for PBRM1-deficient ccRCC.