The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Dysregulation of Hippo-YAP1 signaling promotes initiation and progression of several types of cancer, including gastric cancer (GC). As the Hippo-YAP1 pathway regulates expression of thousands of genes, it is important to establish which target genes contribute to the oncogenic program driven by YAP1 to identify strategies to circumvent it. Here, we identified a vital role of FOXP4 in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired GC spheroid formation and reduced stemness marker expression, while FOXP4 upregulation potentiated cancer cell stemness. RNA-seq analysis revealed SOX12 as downstream target of FOXP4, and functional studies established that SOX12 supports stemness in YAP1-induced carcinogenesis. A small molecule screen identified 42-(2-Tetrazolyl)rapamycin as a FOXP4 inhibitor, and targeting FOXP4 suppressed GC tumor growth and enhanced the efficacy of 5-FU chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in GC regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1-FOXP4-SOX12 axis represents a potential therapeutic strategy for GC.

中文翻译：

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FOXP4 是促进胃癌干性并驱动转移的直接 YAP1 靶点


Hippo-YAP1 通路是一种进化上保守的信号级联反应，可控制器官大小和组织再生。Hippo-YAP1 信号转导失调促进多种癌症的发生和进展，包括胃癌 （GC）。由于 Hippo-YAP1 通路调节数千个基因的表达，因此确定哪些靶基因有助于 YAP1 驱动的致癌程序，以确定规避它的策略非常重要。在这里，我们确定了 FOXP4 通过维持干性和促进腹膜转移在 YAP1 驱动的胃癌发生中的重要作用。FOXP4 的缺失损害了 GC 球体的形成并降低了干性标志物的表达，而 FOXP4 上调增强了癌细胞的干性。RNA-seq 分析显示 SOX12 是 FOXP4 的下游靶标，功能研究确定 SOX12 支持 YAP1 诱导的致癌作用的干性。小分子筛选发现 42-（2-四唑基）雷帕霉素是一种 FOXP4 抑制剂，靶向 FOXP4 抑制了 GC 肿瘤生长并增强了 5-FU 化疗的体内疗效。总的来说，这些发现揭示了 GC 中 YAP1 的 FOXP4 上调通过上调 SOX12 来调节干性和肿瘤发生。靶向 YAP1-FOXP4-SOX12 轴代表了 GC 的潜在治疗策略。