VHL synthetic lethality screens uncover CBF-β as a negative regulator of STING

Abstract

SummaryClear 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 ofVHL, and uncover that loss of Core Binding Factor β (CBF-β) causes cell death inVHL-null ccRCC cell lines and impairs tumour establishment and growthin vivo. This synthetic relationship is independent of the elevated activity of hypoxia inducible factors (HIFs) inVHL-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 theSTINGlocus 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.