UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma

Abstract KRAS is one of the most frequently mutated oncogenes in lung cancer. To identify novel KRAS-specific vulnerabilities, we performed RNAi screens in spheroid cultures of primary tumor cells derived from a mouse model of lung cancer driven by activation of Kras and loss of p53. Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1), an epigenetic regulator involved in DNA methylation, was identified as a gene selectively important for the 3D growth of primary tumor cells derived from this model. Further studies in human lung cancer cell lines confirmed that UHRF1 knock-out selectively impaired sphere growth and induced apoptosis in cells expressing oncogenic KRAS but had minimal effect on KRAS wild type or non-transformed lung cells. To understand its KRAS-specific role, we depleted UHRF1 in KRAS mutant lung cancer cell lines and analyzed genome-wide methylation and gene expression. UHRF1 loss led to global DNA hypomethylation resulting in the upregulation of lung cancer-specific tumor suppressor genes (TSGs). The majority of these TSGs were also overexpressed after KRAS loss, suggesting a mechanistic link between UHRF1 and KRAS-driven oncogenic phenotypes. In vivo, UHRF1 knock-out impaired tumor growth in mouse models of KRAS-driven lung cancer. Finally, analysis of lung cancer patient data revealed that high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with tumors harboring KRAS mutations. These results in human cells and mouse models identify UHRF1 as a KRAS-specific vulnerability and a potential target for therapeutic intervention.