FOXP4 Is a Direct YAP1 Target That Promotes Gastric Cancer Stemness and Drives Metastasis

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• The Hippo-YAP1 pathway is crucial for organ size and regeneration.
• Its dysregulation is implicated in gastric cancer initiation and progression.
• Identifying YAP1 target genes is key to understanding and circumventing oncogenic programs.

Purpose of the Study:

• To investigate the role of forkhead box protein 4 (FOXP4) in YAP1-driven gastric carcinogenesis.
• To identify downstream targets of FOXP4 that contribute to cancer stemness.
• To explore therapeutic strategies targeting the YAP1-FOXP4 axis.

Main Methods:

• RNA sequencing to identify downstream targets.
• Functional studies to assess stemness and spheroid formation.
• Small-molecule screening to identify FOXP4 inhibitors.
• In vivo studies to evaluate therapeutic efficacy.

Main Results:

• FOXP4 is vital for YAP1-driven gastric cancer, maintaining stemness and promoting metastasis.
• Loss of FOXP4 impairs cancer stemness; its upregulation potentiates it.
• SOX12 was identified as a downstream target of FOXP4, supporting stemness.
• A FOXP4 inhibitor suppressed tumor growth and enhanced chemotherapy efficacy in vivo.

Conclusions:

• YAP1 upregulates FOXP4 in gastric cancer, which in turn upregulates SOX12 to maintain stemness and tumorigenesis.
• The YAP1-FOXP4-SOX12 axis is a potential therapeutic target for gastric cancer.
• FOXP4 serves as a stemness biomarker and therapeutic target for improving patient outcomes.