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

Overview

Journal Cancer Res

Specialty Oncology

Date 2024 Jul 24

PMID 39047223

Authors

Xiaoli Liu

Bonan Chen

Fuda Xie

Kit Yee Wong

Alvin H K Cheung

Jinglin Zhang

Qian Wu

Canbin Fang

Jintao Hu

Shouyu Wang

Dazhi Xu

Jianwu Chen

Yuzhi Wang

Chi Chun Wong

Huarong Chen

William K K Wu

Jun Yu

Michael W Y Chan

Chi Man Tsang

Kwok Wai Lo

Gary M K Tse

Ka-Fai To

Wei Kang

Affiliations

Soon will be listed here.

Abstract

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. 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. In this study, we identified a vital role of forkhead box protein 4 (FOXP4) in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired gastric cancer spheroid formation and reduced stemness marker expression, whereas FOXP4 upregulation potentiated cancer cell stemness. RNA sequencing analysis revealed SOX12 as a 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 gastric cancer tumor growth and enhanced the efficacy of 5-fluorouracil chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in gastric cancer regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1-FOXP4-SOX12 axis represents a potential therapeutic strategy for gastric cancer. Significance: Hippo-YAP1 signaling maintains stemness in gastric cancer by upregulating FOXP4, identifying FOXP4 as a stemness biomarker and therapeutic target that could help improve patient outcomes.

Citing Articles

Educational Review: Updates on Therapeutic Strategies for Gastric Cancer with Peritoneal Metastasis.

Lewis K, Diggs L, Badgwell B Ann Surg Oncol. 2025; .

PMID: 40016614 DOI: 10.1245/s10434-025-17069-3.

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