| First Author | Kostyrko K | Year | 2023 |
| Journal | Nat Commun | Volume | 14 |
| Issue | 1 | Pages | 3966 |
| PubMed ID | 37407562 | Mgi Jnum | J:337993 |
| Mgi Id | MGI:7508518 | Doi | 10.1038/s41467-023-39591-2 |
| Citation | Kostyrko K, et al. (2023) UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma. Nat Commun 14(1):3966 |
| abstractText | 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. |
