{"title":"FKH domain-mediated nuclear FOXP3 suppresses gastric cancer malignancy via c-MYC/CDKN1A regulation, EMT inhibition, and PI3K/AKT signaling modulation.","authors":"Yu Chen, Xia Zhao, Yuze Zhu, Ling Xu, Juanjuan Wang, Zheyi Chen, Hui Chen, Tingting Rong, Yanhui Ma, Yi Liu, Yunlan Zhou, Yingxia Zheng, Lisong Shen, Guohua Xie","doi":"10.1007/s11010-025-05387-9","DOIUrl":null,"url":null,"abstract":"<p><p>Gastric cancer (GC) remains a primary contributor to cancer-associated deaths worldwide, especially in East Asia. We investigated the function of nuclear-localized full-length FOXP3 (FOXP3FL) as an oncosuppressive factor in GC. Total FOXP3 was markedly reduced in GC tissues versus adjacent normal mucosa, with distinct cytoplasmic and nuclear patterns. Functional assays revealed that nuclear overexpression of FOXP3FL suppresses proliferation, migration, and invasion of GC cells in vitro and in vivo and promotes cellular senescence in vivo. Mechanistically, FOXP3FL directly represses MYC transcription and induces CDKN1A, thereby restraining proliferation and metastasis. These transcriptional changes, together with concomitant PTEN upregulation and PI3K-P110α downregulation, collectively attenuate PI3K/AKT signaling and impair epithelial-mesenchymal transition (EMT) in FOXP3FL-expressing GC cells. The forkhead (FKH) domain is essential: its deletion yields cytoplasmic FOXP3ΔFKH, which loses transcriptional control and antitumor activity. Our findings underscore nuclear-localized FOXP3FL as a tumor suppressor whose FKH domain is integral to its suppressive function.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular and Cellular Biochemistry","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s11010-025-05387-9","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Gastric cancer (GC) remains a primary contributor to cancer-associated deaths worldwide, especially in East Asia. We investigated the function of nuclear-localized full-length FOXP3 (FOXP3FL) as an oncosuppressive factor in GC. Total FOXP3 was markedly reduced in GC tissues versus adjacent normal mucosa, with distinct cytoplasmic and nuclear patterns. Functional assays revealed that nuclear overexpression of FOXP3FL suppresses proliferation, migration, and invasion of GC cells in vitro and in vivo and promotes cellular senescence in vivo. Mechanistically, FOXP3FL directly represses MYC transcription and induces CDKN1A, thereby restraining proliferation and metastasis. These transcriptional changes, together with concomitant PTEN upregulation and PI3K-P110α downregulation, collectively attenuate PI3K/AKT signaling and impair epithelial-mesenchymal transition (EMT) in FOXP3FL-expressing GC cells. The forkhead (FKH) domain is essential: its deletion yields cytoplasmic FOXP3ΔFKH, which loses transcriptional control and antitumor activity. Our findings underscore nuclear-localized FOXP3FL as a tumor suppressor whose FKH domain is integral to its suppressive function.
期刊介绍:
Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell.
In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.