Loss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis

Judit Espana-Agusti, Anne Warren, Su Kit Chew, David J. Adams and Athena Matakidou ()
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Judit Espana-Agusti: University of Cambridge, CRUK Cambridge institute
Anne Warren: Addenbrooke’s Hospital
Su Kit Chew: Wellcome Trust Sanger Institute
David J. Adams: Wellcome Trust Sanger Institute
Athena Matakidou: University of Cambridge, CRUK Cambridge institute

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Inactivation of the VHL (Von Hippel Lindau) tumour suppressor has long been recognised as necessary for the pathogenesis of clear cell renal cancer (ccRCC); however, the molecular mechanisms underlying transformation and the requirement for additional genetic hits remain unclear. Here, we show that loss of VHL alone results in DNA replication stress and damage accumulation, effects that constrain cellular growth and transformation. By contrast, concomitant loss of the chromatin remodelling factor PBRM1 (mutated in 40% of ccRCC) rescues VHL-induced replication stress, maintaining cellular fitness and allowing proliferation. In line with these data we demonstrate that combined deletion of Vhl and Pbrm1 in the mouse kidney is sufficient for the development of fully-penetrant, multifocal carcinomas, closely mimicking human ccRCC. Our results illustrate how VHL and PBRM1 co-operate to drive renal transformation and uncover replication stress as an underlying vulnerability of all VHL mutated renal cancers that could be therapeutically exploited.

Date: 2017
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DOI: 10.1038/s41467-017-02245-1

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