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

Xiaoli Liu1,2,3, Bonan Chen1,2,3, Fuda Xie1,2,3

  • 1Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.

Cancer Research
|July 24, 2024
PubMed

Insights

The Hippo-YAP1 pathway drives gastric cancer by upregulating forkhead box protein 4 (FOXP4), which maintains cancer stemness and promotes metastasis. Targeting FOXP4 offers a new therapeutic strategy for gastric cancer.

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.

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