UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma

Kaja Kostyrko (), Marta Román, Alex G. Lee, David R. Simpson, Phuong T. Dinh, Stanley G. Leung, Kieren D. Marini, Marcus R. Kelly, Joshua Broyde, Andrea Califano, Peter K. Jackson and E. Alejandro Sweet-Cordero ()
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Kaja Kostyrko: University of California, San Francisco
Marta Román: University of California, San Francisco
Alex G. Lee: University of California, San Francisco
David R. Simpson: University of California, San Francisco
Phuong T. Dinh: University of California, San Francisco
Stanley G. Leung: University of California, San Francisco
Kieren D. Marini: University of California, San Francisco
Marcus R. Kelly: Stanford University School of Medicine
Joshua Broyde: Columbia University
Andrea Califano: Columbia University
Peter K. Jackson: Stanford University School of Medicine
E. Alejandro Sweet-Cordero: University of California, San Francisco

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention.

Date: 2023
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DOI: 10.1038/s41467-023-39591-2

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