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Therapeutic targeting of FUBP3 phase separation by GATA2-AS1 inhibits malate-aspartate shuttle and neuroblastoma
Xiaojing Wang1,2, Yanhua Guo1, Guo Chen1
1Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, P. R. China.
Abstract:
Malate-aspartate shuttle (MAS) is essential for maintaining glycolysis and energy metabolism in tumors, while its regulatory mechanisms in neuroblastoma (NB), the commonest extracranial malignancy during childhood, still remain to be elucidated. Herein, by analyzing multi-omics data, GATA binding protein 2 (GATA2) and its antisense RNA 1 (GATA2-AS1) were identified to suppress MAS during NB progression. Mechanistic studies revealed that GATA2 inhibited the transcription of glutamic-oxaloacetic transaminase 2 (GOT2) and malate dehydrogenase 2 (MDH2). As a long non-coding RNA destabilized by RNA binding motif protein 15-mediated N6-methyladenosine methylation, GATA2-AS1 bound with far upstream element binding protein 3 (FUBP3) to repress its liquid-liquid phase separation and interaction with suppressor of zest 12 (SUZ12), resulting in decrease of SUZ12 activity and epigenetic up-regulation of GATA2 and other tumor suppressors. Rescue experiments revealed that GATA2-AS1 inhibited MAS and NB progression via repressing interaction between FUBP3 and SUZ12. Pre-clinically, administration of lentivirus carrying GATA2-AS1 suppressed MAS, aerobic glycolysis, and aggressive behaviors of NB xenografts. Notably, low GATA2-AS1 or GATA2 expression and high FUBP3, SUZ12, GOT2 or MDH2 levels were linked with unfavorable outcome of NB patients. These findings suggest that GATA2-AS1 inhibits FUBP3 phase separation to repress MAS and NB progression via modulating SUZ12 activity.
Insights
GATA2-AS1 suppresses neuroblastoma progression by inhibiting the malate-aspartate shuttle (MAS). This long non-coding RNA impacts FUBP3 phase separation, affecting SUZ12 activity and tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- The malate-aspartate shuttle (MAS) is crucial for tumor energy metabolism.
- Regulatory mechanisms of MAS in neuroblastoma (NB) are not fully understood.
- Identifying novel regulators of MAS in NB is critical for therapeutic development.
Purpose of the Study:
- To elucidate the role of GATA binding protein 2 (GATA2) and its antisense RNA 1 (GATA2-AS1) in regulating MAS in neuroblastoma.
- To investigate the molecular mechanisms by which GATA2-AS1 influences NB progression.
- To assess the therapeutic potential of targeting GATA2-AS1 in NB.
Main Methods:
- Multi-omics data analysis to identify key regulatory molecules.
- Mechanistic studies including gene transcription, RNA-protein interactions, and liquid-liquid phase separation assays.
- In vivo experiments using NB xenografts and analysis of patient data.
Main Results:
- GATA2 and GATA2-AS1 were identified as suppressors of MAS in NB.
- GATA2-AS1 inhibits MAS and NB progression by repressing FUBP3-SUZ12 interaction and SUZ12 activity.
- GATA2-AS1 administration suppressed NB xenograft growth, aerobic glycolysis, and aggressive behaviors.
- Low GATA2-AS1/GATA2 and high FUBP3/SUZ12/GOT2/MDH2 levels correlate with poor NB patient outcomes.
Conclusions:
- GATA2-AS1 acts as a tumor suppressor in neuroblastoma by inhibiting the malate-aspartate shuttle.
- GATA2-AS1 exerts its function by modulating FUBP3 phase separation and SUZ12 activity, impacting epigenetic regulation.
- GATA2-AS1 represents a potential therapeutic target for neuroblastoma treatment.
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