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- Title
UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma.
- Authors
Kostyrko, Kaja; Román, Marta; Lee, Alex G.; Simpson, David R.; Dinh, Phuong T.; Leung, Stanley G.; Marini, Kieren D.; Kelly, Marcus R.; Broyde, Joshua; Califano, Andrea; Jackson, Peter K.; Alejandro Sweet-Cordero, E.
- 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.Identifying KRAS-specific vulnerabilities helps to target KRAS-driven cancer. Here the authors perform RNA interference screens in 3D cultures of primary tumour cells with KRAS activation and p53 loss and identify UHRF1 as a vulnerability of KRAS-mutant lung cancers
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-39591-2