VHL synthetic lethality screens uncover CBF-β as a negative regulator of STING
James A. C. Bertlin, Tekle Pauzaite, Qian Liang, Niek Wit, James C. Williamson, Jia Jhing Sia, Nicholas J. Matheson, Brian M. Ortmann, Thomas J. Mitchell, Anneliese O. Speak, Qing Zhang, James A. Nathan
Abstract
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.