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VHL synthetic lethality screens uncover CBF-β as a negative regulator of STING
James A C Bertlin1, Tekle Pauzaite1, Qian Liang2
1Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Department of Medicine, University of Cambridge, Cambridge, UK.
Abstract:
Clear cell renal cell carcinoma (ccRCC) represents the most common form of kidney cancer and is typified by biallelic inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene. Here, we undertake genome-wide CRISPR/Cas9 screening to reveal synthetic lethal interactors of VHL, and uncover that loss of Core Binding Factor β (CBF-β) causes cell death in VHL-null ccRCC cell lines and impairs tumour establishment and growth in vivo. This synthetic relationship is independent of the elevated activity of hypoxia inducible factors (HIFs) in VHL-null cells, but does involve the RUNX transcription factors that are known binding partners of CBF-β. Mechanistically, CBF-β loss leads to upregulation of type I interferon signalling, and we uncover a direct inhibitory role for CBF-β at the STING locus controlling Interferon Stimulated Gene expression. Targeting CBF-β in kidney cancer both selectively induces tumour cell lethality and promotes activation of type I interferon signalling.
Insights
Loss of Core Binding Factor β (CBF-β) selectively kills clear cell renal cell carcinoma (ccRCC) cells lacking the von Hippel-Lindau (VHL) gene. This discovery offers a new therapeutic strategy for VHL-deficient kidney cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer subtype.
- VHL tumor suppressor gene inactivation is a hallmark of ccRCC.
- Understanding VHL's synthetic lethal interactors is crucial for targeted therapies.
Purpose of the Study:
- To identify genes that are synthetically lethal with VHL loss using genome-wide CRISPR/Cas9 screening.
- To investigate the role of Core Binding Factor β (CBF-β) in VHL-null ccRCC.
- To elucidate the mechanism by which CBF-β loss affects ccRCC cells.
Main Methods:
- Genome-wide CRISPR/Cas9 screening in VHL-null ccRCC cell lines.
- In vivo studies to assess tumor establishment and growth.
- Analysis of gene expression, including type I interferon signaling and Interferon Stimulated Genes (ISGs).
- Investigation of the STING locus and its regulation by CBF-β.
Main Results:
- Loss of CBF-β leads to cell death in VHL-null ccRCC cells.
- CBF-β loss impairs tumor growth in vivo.
- The synthetic lethality is independent of hypoxia-inducible factors (HIFs) but involves RUNX transcription factors.
- CBF-β loss upregulates type I interferon signaling by directly inhibiting the STING locus, controlling ISG expression.
Conclusions:
- CBF-β is a synthetic lethal interactor of VHL in ccRCC.
- Targeting CBF-β selectively induces lethality in ccRCC cells.
- CBF-β inhibition activates type I interferon signaling, presenting a novel therapeutic avenue for kidney cancer.
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