The team of Professor Eveline Barbieri of Baylor College of Medicine in the United States AS: CHAF1A blocks neuronal differentiation through metabolic reprogramming and promotes the occurrence of neuroblastoma

During embryonic development, a group of stem cells at the edge of the neural plate can be induced to become neural crest cells (NCCs), which undergo colonization, epithelial-mesenchymal transition, migration, and finally differentiate into neurons and glial cells of the peripheral nervous system.
facial cartilage and bone, as well as melanoma cells
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Studies have shown that the interruption of neural crest differentiation can lead to the malignant transformation of neuro-ectoderm precursor cells, and eventually neuroblastoma (NB), but the mechanism is not clear
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The current treatment for neuroblastoma is generally to take retinoic acid (RA), but some patients are not sensitive to drugs
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Recently, the team of Professor Eveline Barbieri of Baylor College of Medicine in the United States found that chromatin assembly factor 1A (CHAF1A) regulates the development, proliferation, differentiation, and expression of metabolic-related genes, thereby limiting zebrafish neural crest cells and human nerves.
The neuron differentiation of crest cells, and this process is an important cause of neuroblastoma
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In addition, CHAF1A can activate polyamine metabolism, thereby blocking the differentiation of NB.
Blocking polyamine synthesis can restore RA-mediated neuronal differentiation and increase the sensitivity of cells to RA, indicating that targeted polyamine metabolism is a kind of A new strategy to improve the therapeutic effect of RA in patients with clinical neuroblastoma
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Related results "CHAF1A Blocks Neuronal Differentiation and Promotes Neuroblastoma Oncogenesis via Metabolic Reprogramming" were published in Advanced Science
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CHAF1A is a subunit (p150) in the chromatin assembly factor 1 (CAF-1) nuclear complex, in addition to CHAF1B (p60) and p48 subunits
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As a histone chaperone, CAF-1 controls nucleosome assembly, maintenance of heterochromatin and DNA repair, while CHAF1A, as the main subunit of CAF-1, plays a central role in the normal functioning of the latter
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CHAF1A is very important for embryonic development.
In mouse and Drosophila models, the loss of CHAF1A homozygous mutation often leads to developmental arrest.
In addition, the high expression of CHAF1A is associated with breast cancer, squamous cell carcinoma, and Src transformation of epithelial cells.
Related
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The team’s previous studies confirmed that the high expression of CHAF1A in NB patients often means a poor prognosis, while inhibiting the function of CHAF1A promotes NB cell differentiation and blocks tumor growth
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Therefore, the author first used neuroblastoma SHEP cells to overexpress CHAF1A and found that it can promote tumor cell proliferation, migration and invasion
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Cohort studies of NB patients and in vitro cell studies are consistent with this conclusion
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In view of the existing evidence that RA is effective in treating neuroblastoma, the authors further explored the role of CHAF1A in RA-induced neuronal differentiation
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Construct NGP-CHAF1A cells that conditionally up-regulate CHAF1A.
After RA treatment, MNA NGP cells no longer proliferate and axons grow outward, tending to differentiate, while NGP overexpressing CHAF1A shows differentiation inhibition
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Next, using the zebrafish embryo model, the authors found that CHAF1A was expressed in the neuroepithelium in the early embryonic stage.
As the development progresses, non-neuronal NCC co-expresses CHAF1A and MYCN, but the expression is reduced in neuronal NCC, that is, CHAF1A and MYCN is co-expressed in undifferentiated NCC, but not in differentiated ganglia, indicating that the loss of CHAF1A and MYCN is a necessary condition for NCC to differentiate into neuronal lineage
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Through gene expression profiling analysis of SHEP cells overexpressing CHAF1A, GO enrichment analysis found that the 416 genes with differences were mostly concentrated in development, differentiation, proliferation, and metabolism-related pathways, indicating that CHAF1A overexpression ultimately leads to transcriptional changes, which leads to Differentiation and metabolic reprogramming are limited
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By non-targeted metabonomic analysis of SHEP cells that conditionally overexpress CHAF1A, it is found that CHAF1A induces up-regulation of pyrimidine, polyamine, and polyunsaturated fatty acid metabolic pathways, while down-regulation of sphingolipids, acylcarnitine-related fatty acids, and phenylpropanine.
Metabolic pathways of acid and tyrosine
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Among them, the polyamine metabolic pathway continues to be enriched
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Further; silencing the CHAF1A gene under IMR32 cell conditions found that polyamine metabolism was significantly down-regulated, indicating that CHAF1A can activate polyamine biosynthesis to maintain cell growth
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Therefore, the authors used the ornithine decarboxylase 1 (ODC1) inhibitor DFMO to inhibit spermine metabolism and found that it almost completely reversed the RA-induced neural differentiation blocked by CHAF1A, which also shows that CHAF1A blocks the synthesis of polyamines by up-regulating it.
Cells differentiate and promote cell cycle progression
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The same conclusion was obtained using IMR32 cells overexpressing ODC1
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At the end of the article, the author used the NB orthotopic xenotransplantation mouse model to verify the efficacy of DFMO+RA combined treatment of NB in ​​vivo
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The results found that DFMO+RA can significantly inhibit tumor growth and promote cell apoptosis, thus confirming that targeting CHAF1A or CHAF1A-induced polyamine metabolism can effectively enhance RA activity, which provides a clinical application of DFMO+RA in the treatment of neuroblastoma A strong theoretical basis
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WILEY References: Tao L, Moreno-Smith M, Ibarra-García-Padilla R, et al.
CHAF1A Blocks Neuronal Differentiation and Promotes Neuroblastoma Oncogenesis via Metabolic Reprogramming.
Adv Sci (Weinh).
2021 Oct;8(19):e2005047.
doi: 10.
1002/advs.
202005047.
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