BRCA1-associated protein 1 (BAP1) loss reduced type I interferon signaling in a xenograft model of clear cell renal cell carcinoma (ccRCC), and reactivation of this pathway using a small molecule agonist enhanced suppression of BAP1-deficient tumor growth, according to research presented at the International Kidney Cancer Symposium (IKCS) 2021.
Patients with BAP1-mutant ccRCC have very poor prognosis and comprise 10% to 15% of ccRCC cases, and BAP1-targeted therapies have not yet been developed.
To gain insight into the mechanism of BAP1 tumor suppression, the investigators studied how BAP1 regulates interferon stimulated gene factor (ISGF) 3, which is involved in inducing tumor suppression. They also tested whether ISGF3 activation by a stimulator of interferon genes (STING) agonist can inhibit BAP1-deficient tumor growth.
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The team manipulated various genes of interest in ccRCC cells and performed xenograft analyses to assess whether genetic change or treatment compound can alter tumor growth. They also evaluated the importance of the deubiquitinase activity of BAP1 for ISGF3 regulation.
The studies showed that Von Hippel–Lindau (VHL) tumor suppressor and hypoxia-inducible factor (HIF) 2α regulate IFN-β expression in ccRCC cells and that IFN-β activates ISGF3 and suppresses tumor growth in the xenograft model.
Transcriptional analysis showed that ISGF3 activity appears to be regulated in a BAP1 deubiquitinase-dependent manner, and BAP1 upregulates IFN-β and stimulates ISGF3 activity, which occurs through STING activation. Treatment of mice with BAP1-deficient xenograft tumors with a STING agonist increased ISGF3 activity and slowed tumor growth.
“BAP1 is a bona fide ccRCC tumor suppressor,” concluded the authors. “BAP1 loss-of-function would lead to reduced STING expression and IFN-β, thus crippling the tumor-suppressive pathway… Reactivation of this pathway may benefit ccRCC patients harboring BAP 1 mutations.”
Reference
Langbein L, El Hajjar R, He S, et al. BAP1 suppresses tumor growth via interferon beta and ISGF3 in clear cell renal cell carcinoma. Presented at IKCS 2021; November 5-6, 2021. Abstract N34.
