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Published on: April 22, 2017
BML-281 promotes neuronal differentiation by modulating Wnt/Ca2+ and Wnt/PCP signaling pathway
Jiyun Choi1, Seoyeon Gang1,2, Mahesh Ramalingam1
1Department of Physiology, Chonnam National University Medical School, Jellanamdo, 58128, Republic of Korea.
Abstract:
Histone deacetylase (HDAC) inhibitors promote differentiation through post-translational modifications of histones. BML-281, an HDAC6 inhibitor, has been known to prevent tumors, acute dextran sodium sulfate-associated colitis, and lung injury. However, the neurogenic differentiation effect of BML-281 is poorly understood. In this study, we investigated the effect of BML-281 on neuroblastoma SH-SY5Y cell differentiation into mature neurons by immunocytochemistry (ICC), reverse transcriptase PCR (RT-PCR), quantitative PCR (qPCR), and western blotting analysis. We found that the cells treated with BML-281 showed neurite outgrowth and morphological changes into mature neurons under a microscope. It was confirmed that the gene expression of neuronal markers (NEFL, MAP2, Tuj1, NEFH, and NEFM) was increased with certain concentrations of BML-281. Similarly, the protein expression of neuronal markers (NeuN, Synaptophysin, Tuj1, and NFH) was upregulated with BML-281 compared to untreated cells. Following treatment with BML-281, the expression of Wnt5α increased, and downstream pathways were activated. Interestingly, both Wnt/Ca2+ and Wnt/PCP pathways activated and regulated PKC, Cdc42, RhoA, Rac1/2/3, and p-JNK. Therefore, BML-281 induces the differentiation of SH-SY5Y cells into mature neurons by activating the non-canonical Wnt signaling pathway. From these results, we concluded that BML-281 might be a novel drug to differentiation into neuronal cells through the regulation of Wnt signaling pathway to reduce the neuronal cell death.
Insights
BML-281, a histone deacetylase 6 (HDAC6) inhibitor, promotes neuroblastoma cell differentiation into mature neurons. This occurs via activation of the Wnt signaling pathway, suggesting potential therapeutic applications for neuronal cell death.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Histone deacetylase (HDAC) inhibitors influence cell differentiation through histone modifications.
- BML-281, an HDAC6 inhibitor, has demonstrated protective effects against various injuries but its role in neurogenesis is unclear.
- Neuroblastoma SH-SY5Y cells are a common model for studying neuronal differentiation.
Purpose of the Study:
- To investigate the effect of BML-281 on the differentiation of neuroblastoma SH-SY5Y cells into mature neurons.
- To elucidate the underlying molecular mechanisms, particularly the involvement of the Wnt signaling pathway.
Main Methods:
- Neuroblastoma SH-SY5Y cells were treated with BML-281.
- Immunocytochemistry (ICC), RT-PCR, qPCR, and Western blotting were used to assess neuronal differentiation markers.
- Wnt signaling pathway activation was analyzed.
Main Results:
- BML-281 treatment induced neurite outgrowth and morphological changes indicative of neuronal differentiation.
- Gene and protein expression of key neuronal markers (e.g., NEFL, MAP2, Tuj1, NeuN, Synaptophysin) were significantly upregulated.
- BML-281 activated the non-canonical Wnt signaling pathway, including Wnt/Ca2+ and Wnt/PCP pathways, leading to the regulation of downstream effectors like RhoA, Rac1/2/3, and p-JNK.
Conclusions:
- BML-281 effectively induces neuronal differentiation in SH-SY5Y cells.
- The mechanism involves the activation of the non-canonical Wnt signaling pathway.
- BML-281 shows promise as a therapeutic agent for promoting neuronal differentiation and potentially reducing neuronal cell death.
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