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

Elife. 2018 Oct 25;7:e37925. doi: 10.7554/eLife.37925.

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.

Keywords: BAP1; ISGF3; KDM5C; PBRM1; VHL; cancer biology; chromosomes; gene expression; human; kidney cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Carcinoma, Renal Cell / pathology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Feedback, Physiological
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Genes, Tumor Suppressor*
  • Heterografts
  • Humans
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / metabolism*
  • Kidney Neoplasms / pathology*
  • Mice, Nude
  • Neoplasm Transplantation
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • IRF9 protein, human
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • endothelial PAS domain-containing protein 1
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human