Related Experiment Video
Updated: Jul 4, 2026
Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016
RUNX3 cooperates with FoxO3a to induce apoptosis in gastric cancer cells
Yasuko Yamamura1, Wei Lin Lee, Ken-ichi Inoue
1Oncology Research Institute, National University Medical Institutes, Institute of Molecular and Cell Biology, Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 117592, Singapore.
Abstract:
The transcription factor RUNX3, which mediates apoptosis and cell growth inhibition in gastric epithelial cells, is a candidate tumor suppressor that is frequently lost in gastric cancer cells. Here, we found that restoration of RUNX3 expression in the cell line not expressing RUNX3 induced apoptosis and that it physically interacted with the Forkhead transcription factor FoxO3a/FKHRL1, known to be an important regulator of apoptosis and the cell cycle. Active unphosphorylated FoxO3a/FKHRL1 was expressed in the gastric cancer cell lines. RUNX3-induced apoptosis depended on the expression of Bim, a proapoptotic BH3-only protein, and both RUNX3 and FoxO3a/FKHRL1 were required for induction of Bim expression. Furthermore, we showed that interaction of RUNX3 and FoxO3a/FKHRL1 was also indispensable for Bim expression and apoptosis in mouse embryonic fibroblasts. In the Bim promoter, RUNX3 bound to two conserved RUNX-binding elements (RBE1 and RBE2), with RBE1 being immediately downstream of a FoxO-binding element. The physical interaction of RUNX3 and FoxO3a/FKHRL1 on the Bim promoter activated transcription of Bim. These findings show that RUNX3 cooperates with FoxO3a/FKHRL1 to participate in the induction of apoptosis by activating Bim and may play an important role in tumor suppression in gastric cancer.
Insights
RUNX3, a tumor suppressor, induces apoptosis in gastric cancer cells by interacting with FoxO3a/FKHRL1. This interaction activates Bim expression, crucial for tumor suppression.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- RUNX3 is a candidate tumor suppressor frequently lost in gastric cancer.
- RUNX3 normally mediates apoptosis and inhibits cell growth in gastric epithelial cells.
Purpose of the Study:
- To investigate the mechanism by which RUNX3 suppresses gastric cancer.
- To elucidate the interaction between RUNX3 and FoxO3a/FKHRL1 in apoptosis induction.
Main Methods:
- Restoration of RUNX3 expression in RUNX3-negative gastric cancer cells.
- Co-immunoprecipitation to assess protein interactions.
- Western blotting to detect protein expression.
- Reporter assays to analyze promoter activity.
Main Results:
- Restored RUNX3 expression induced apoptosis in gastric cancer cells.
- RUNX3 physically interacted with FoxO3a/FKHRL1, a known apoptosis regulator.
- RUNX3 and FoxO3a/FKHRL1 co-operatively activated Bim expression, a proapoptotic protein.
- RUNX3 bound to the Bim promoter elements, enhancing transcription in conjunction with FoxO3a/FKHRL1.
Conclusions:
- RUNX3 cooperates with FoxO3a/FKHRL1 to induce apoptosis via Bim activation.
- This RUNX3-FoxO3a/FKHRL1-Bim pathway is critical for tumor suppression in gastric cancer.
