UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma.

Autor: Kostyrko K; Division of Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA. kaja.kostyrko@ucsf.edu., Román M; Division of Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA., Lee AG; Division of Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA., Simpson DR; Division of Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA., Dinh PT; Division of Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA., Leung SG; Division of Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA., Marini KD; Division of Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA., Kelly MR; Baxter Laboratory, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA., Broyde J; Department of Systems Biology, Columbia University, New York, NY, USA., Califano A; Department of Systems Biology, Columbia University, New York, NY, USA.; Department of Biomedical Informatics, Columbia University, New York, NY, USA.; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.; Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA., Jackson PK; Baxter Laboratory, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA., Sweet-Cordero EA; Division of Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA. alejandro.sweet-cordero@ucsf.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Jul 05; Vol. 14 (1), pp. 3966. Date of Electronic Publication: 2023 Jul 05.
DOI: 10.1038/s41467-023-39591-2
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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