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

Bertlin, J. A.; Pauzaite, T.; Liang, Q.; Wit, N.; Williamson, J. C.; Sia, J. J.; Matheson, N. J.; Ortmann, B. M.; Mitchell, T. J.; Speak, A. O.; Zhang, Q.; Nathan, J. A.

doi:10.1101/2024.09.03.610968

bioRxiv · 10.1101/2024.09.03.610968

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

Bertlin, J. A.·Pauzaite, T.·Liang, Q.·Wit, N.·Williamson, J. C.·Sia, J. J.·Matheson, N. J.·Ortmann, B. M.·Mitchell, T. J.·Speak, A. O.·Zhang, Q.·Nathan, J. A.

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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 {beta} (CBF-{beta}) 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-{beta}. Mechanistically, CBF-{beta} loss leads to upregulation of type I interferon signalling, and we uncover a direct inhibitory role for CBF-{beta} at the STING locus controlling Interferon Stimulated Gene expression. Targeting CBF-{beta} in kidney cancer both selectively induces tumour cell lethality and promotes activation of type I interferon signalling.

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Bertlin, J. A., Pauzaite, T., Liang, Q., Wit, N., Williamson, J. C., Sia, J. J., Matheson, N. J., Ortmann, B. M., Mitchell, T. J., Speak, A. O., Zhang, Q., Nathan, J. A.. 2024-09-06. VHL synthetic lethality screens uncover CBF-beta as a negative regulator of STING. https://doi.org/10.1101/2024.09.03.610968

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