ArticleOncogene2005
Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity.
Article in Oncogene, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 82 citations in OpenAlex.
- FOXO1-mediated cell cycle arrest enhances osteogenic differentiation of spheroid-cultured human periodontal ligament-derived multipotent mesenchymal stromal cells.Regenerative therapy · 2026Article
- Pharmacogenomic Drug-Target Network Analysis Reveals Similarity Profiles Among FDA-Approved Cancer Drugs.Pharmaceutics · 2025Article
- Targeting the PI3K/AKT/mTOR pathway in lung cancer: mechanisms and therapeutic targeting.Frontiers in pharmacology · 2025Review
- Downregulation of 4-HNE and FOXO4 collaboratively promotes NSCLC cell migration and tumor growth.Cell death & disease · 2024Article
- Therapeutic strategies targeting FOXO transcription factors.Nature reviews. Drug discovery · 2021Review
- A Novel ZNF304/miR-183-5p/FOXO4 Pathway Regulates Cell Proliferation in Clear Cell Renal Carcinoma.Frontiers in oncology · 2021Article
- EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2020Article
- CDK1 dependent phosphorylation of hTERT contributes to cancer progression.Nature communications · 2020Article
- Correlation of constitutive photomorphogenic 1 (COP1) and p27 tumor suppressor protein expression in ovarian cancer.Genes & genomics · 2019Article
- CTCF regulates the FoxO signaling pathway to affect the progression of prostate cancer.Journal of cellular and molecular medicine · 2019Article
- FOXO1 overexpression and loss of pSerine256-FOXO1 expression predicts clinical outcome in esophageal adenocarcinomas.Scientific reports · 2018Article
- Replication of JC Virus DNA in the G144 Oligodendrocyte Cell Line Is Dependent Upon Akt.Journal of virology · 2017Article
- Curcumin Induces p53-Null Hepatoma Cell Line Hep3B Apoptosis through the AKT-PTEN-FOXO4 Pathway.Evidence-based complementary and alternative medicine : eCAM · 2017Article
- MiR-150 promotes cellular metastasis in non-small cell lung cancer by targeting FOXO4.Scientific reports · 2016Article
- Curcumin induces G2/M arrest and triggers apoptosis via FoxO1 signaling in U87 human glioma cells.Molecular medicine reports · 2016Article
- Autophagy and Apoptotic Crosstalk: Mechanism of Therapeutic Resistance in HER2-Positive Breast Cancer.Breast cancer : basic and clinical research · 2016Review
- COP1 enhances ubiquitin-mediated degradation of p27Kip1 to promote cancer cell growth.Oncotarget · 2015Article
- The cell cycle regulator 14-3-3σ opposes and reverses cancer metabolic reprogramming.Nature communications · 2015Article
- Regulating the stability and localization of CDK inhibitor p27(Kip1) via CSN6-COP1 axis.Cell cycle (Georgetown, Tex.) · 2015Article
- Nucleo-cytoplasmic transport as a therapeutic target of cancer.Journal of hematology & oncology · 2014Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The FOXO family of Forkhead transcription factors, regulated by the phosphoinositide-3-kinase-Akt pathway, is involved in cell cycle regulation and apoptosis. Strong expression of HER2, a receptor tyrosine kinase oncogene, in cancers has been associated with a poor prognosis. Recently, FOXO4 was shown to regulate the transcription of the cyclin-dependent kinase inhibitor p27 Kip1 gene directly. Also, we have shown that HER2 promotes mitogenic growth and transformation of cancer cells by downregulation of p27 Kip1. Given the fact that FOXO4 mediates p27 transcription, we hypothesize that an Akt phosphorylation mutant of FOXO4 (FOXO4A3), which maintains the activity to transactivate p27 Kip1, may be used as an anticancer agent for HER2-overexpressing cancers. Here, we applied the FOXO4 gene as a novel anticancer agent for HER2-overexpressing cells under the control of a tetracycline (tet)-regulated gene expression system. Overexpression of FOXO4A3 inhibits HER2-activated cell growth. We found that FOXO4A3 inhibited the kinase activity of protein kinase B/Akt and reversed HER2-mediated p27 mislocation in the cytoplasm. FOXO4A3 expression also led to decreased levels of CSN5, a protein involved in p27 degradation. These data suggest that FOXO4A3 also can regulate p27 post-transcriptionally. In addition, we found that FOXO4A3 sensitized cells to apoptosis induced by the chemotherapeutic agent 2-methoxyestradiol. Most significantly for clinical application, FOXO4A3 expression in HER2-overexpressing cells can be regulated in vivo and reduces the tumor volume in a tumor model. These findings indicate the applicability of employing FOXO4 regulation as a therapeutic intervention in HER2-overexpressing cancers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.