UHRF1 是肺腺癌中 KRAS 驱动的致癌作用的介质。

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

机构信息

Division of Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

Baxter Laboratory, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.

出版信息

Nat Commun. 2023 Jul 5;14(1):3966. doi: 10.1038/s41467-023-39591-2.

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.

KRAS 是肺癌的常见驱动基因。为了鉴定肺癌中 KRAS 特异性的脆弱性，我们在源自 Kras 突变型小鼠肺癌模型的原代球体中进行了 RNAi 筛选，并发现了一种表观遗传调节剂 Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1)。在人类肺癌模型中，UHRF1 敲除仅在 KRAS 突变细胞中选择性地损害生长并诱导细胞凋亡。UHRF1 耗尽的 KRAS 突变细胞的全基因组甲基化和基因表达分析显示，全局 DNA 低甲基化导致肿瘤抑制基因 (TSGs) 的上调。CRISPR/Cas9 焦点筛选验证了这些 TSGs 中的几个作为 UHRF1 驱动肿瘤发生的介质。在体内，UHRF1 敲除抑制了 KRAS 驱动的小鼠肺癌模型的肿瘤生长。最后，在肺癌患者中，UHRF1 的高表达与 TSG 的表达呈负相关，并预测 KRAS 突变肿瘤患者的预后更差。这些结果将 UHRF1 确定为 KRAS 特异性脆弱性和潜在的治疗干预靶点。