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Updated: Feb 17, 2026
Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
Published on: February 21, 2018
FOXO3 upregulates and activates GSDME to trigger myeloma cell pyroptosis
Yaner Wang1,2, Yali Wang1,3, Yaoli Cui1
1Department of Hematology, The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University; Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
Abstract:
Induction of pyroptosis is considered as a novel strategy for the treatment of multiple myeloma, but the potential targets remain unknown. In the present study, we found that GSDME, a key executor of pyroptosis, is the mostly downregulated pyroptosis-related gene in MM cells and its low expression predicts poor prognosis of MM patients. Out of expectation, GSDME transcription is not markedly affected by epigenetic manners in MM cells. In contrast, GSDME expression is controlled by the transcription factor FOXO3. FOXO3 binds to the two recognition sites and upregulates GSDME. Moreover, FOXO3 specifically upregulates the BNIPL family proteins and activates Caspase-3 and GSDME therefore triggering MM cell pyroptosis. In addition, similar to GSDME, FOXO3 is also downregulated in MM and its restoration suppresses myeloma tumor growth. Furthermore, we found corylin, a flavonoid derived from Psoralea Fructus, activates the transcription of both FOXO3 and GSDME. As expected, corylin displays potent anti-MM activity in association with pyroptosis by upregulating FOXO3 and GSDME. In conclusion, FOXO3 is a novel transcription factor of GSDME. Restoration/activation of the FOXO3/GSDME axis could be a promising novel strategy for the treatment of MM.
Insights
The transcription factor FOXO3 regulates GSDME, a key pyroptosis gene, in multiple myeloma (MM). Activating the FOXO3/GSDME pathway, potentially with corylin, offers a new therapeutic strategy for MM.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Pyroptosis induction is a novel strategy for multiple myeloma (MM) treatment.
- Potential molecular targets for pyroptosis induction in MM remain largely unknown.
Purpose of the Study:
- To identify key regulators of pyroptosis in MM.
- To investigate the role of GSDME and its regulatory mechanisms in MM.
- To explore potential therapeutic strategies targeting the identified pathway.
Main Methods:
- Gene expression analysis in MM cells.
- Identification of transcription factor binding sites.
- Western blotting to assess protein levels.
- In vitro and in vivo studies using MM models.
- Treatment with corylin, a natural flavonoid.
Main Results:
- GSDME, a pyroptosis executor, is downregulated in MM and predicts poor prognosis.
- FOXO3 acts as a transcription factor for GSDME, upregulating its expression.
- FOXO3 also upregulates BNIPL proteins, activating Caspase-3 and GSDME, inducing pyroptosis.
- Both GSDME and FOXO3 are downregulated in MM; FOXO3 restoration suppresses tumor growth.
- Corylin activates FOXO3 and GSDME transcription, exhibiting anti-MM activity via pyroptosis.
Conclusions:
- FOXO3 is a novel transcription factor for GSDME in MM.
- The FOXO3/GSDME axis is crucial for MM cell pyroptosis.
- Restoration or activation of the FOXO3/GSDME pathway presents a promising therapeutic strategy for MM.
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