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Updated: Aug 31, 2025

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BAP1 maintains HIF-dependent interferon beta induction to suppress tumor growth in clear cell renal cell carcinoma

Lauren E Langbein1, Rayan El Hajjar1, Shen He1

  • 1Department of Pathology, Anatomy, & Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States.

Cancer Letters
|August 22, 2022
PubMed

Insights

Loss of BRCA1-associated protein 1 (BAP1) in clear cell renal cell carcinoma (ccRCC) impairs type I interferon signaling. Reactivating this pathway offers a potential therapeutic strategy for ccRCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • BRCA1-associated protein 1 (BAP1) is frequently mutated in clear cell renal cell carcinoma (ccRCC), correlating with poor outcomes.
  • The tumor suppressor functions of BAP1 in ccRCC pathogenesis are not fully understood.
  • Hypoxia-inducible factor 2α (HIF2α) and BAP1 were previously shown to activate interferon-stimulated gene factor 3 (ISGF3), a tumor suppressor in ccRCC models.

Purpose of the Study:

  • To elucidate the mechanisms by which hypoxia-inducible factors (HIF) and BAP1 regulate ISGF3 activity in ccRCC.
  • To investigate the role of type I interferon signaling in BAP1-deficient ccRCC.

Main Methods:

  • Utilized ccRCC cell lines and xenograft models.
  • Investigated gene expression of interferon beta (IFN-β) and stimulator of interferon genes (STING).
  • Assessed ISGF3 activation through overexpression and STING agonist treatment.

Main Results:

  • Loss of the von Hippel-Lindau tumor suppressor (VHL) in ccRCC cells induced IFN-β expression in a HIF2α-dependent manner.
  • IFN-β was essential for ISGF3 activation and inhibited tumor growth in xenografts.
  • BAP1 positively regulated IFN-β and STING expression, thereby enhancing ISGF3 activity.
  • Restoring ISGF3 activity via overexpression or STING agonism suppressed BAP1-deficient tumor growth.

Conclusions:

  • BAP1 loss diminishes type I interferon signaling in ccRCC.
  • Reactivation of the type I interferon pathway presents a promising therapeutic avenue for ccRCC treatment.
Keywords:
BAP1HIFInterferonSTINGccRCC

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