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UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE198450 | GEO | 2023/05/15

REPOSITORIES: GEO

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

Project description: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.

| S-EPMC10322837 | biostudies-literature

UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma [shRNA]

Project description:Using pooled shRNA libraries we performed a focused screen of 115 genes in 3D ex vivo cultures of primary murine lung tumor cells and 2D cultures of murine LKR10 cells. These screens identify Uhrf1 as gene selectively important for the 3D growth of primary lung cancer spheroids.

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UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma [epic_methyl]

Project description:Methylation array was performed to understand the role of UHRF1 in DNA methylation in KRAS mutant lung cancer cell lines. Knock-down of UHRF1 leads to significant changes in global DNA methylation in both cell lines.

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UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma [CRISPR_screen]

Project description:We performed a focused CRISPR in KRAS mutant lung cancer cells (A549) using a minipool sgRNA library targeting 80 lung cancer specific tumor suppressor genes and 12 control genes. This screen identified tumor suppressor genes regulated by Uhrf1 in KRAS mutant lung cancer.

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UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma [RNA-seq]

Project description:RNA sequening was performed to understand the role of UHRF1 in regulation of gene expression in KRAS mutant lung cancer cell lines. Knock-down of both UHRF1 and KRAS leads to significant and overlapping changes in gene expression in both cell lines.

2023-05-15 | GSE198289 | GEO