The antiepileptic and mood stabilizer agent valproic acid (VPA) has been shown to exert anti-tumour effects and to cause neuronal damage in the developing brain through mechanisms not completely understood. In the present study we show that prolonged exposure of SH-SY5Y and LAN-1 human neuroblastoma cells to clinically relevant concentrations of VPA caused a marked induction of the protein and transcript levels of the common neurotrophin receptor p75NTR and its co-receptor sortilin, two promoters of apoptotic cell death in response to proneurotrophins. VPA induction of p75NTR and sortilin was associated with an increase in plasma membrane expression of the receptor proteins and was mimicked by cell treatment with several histone deacetylase (HDAC) inhibitors. VPA and HDAC1 knockdown decreased the level of EZH2, a core component of the polycomb repressive complex 2, and upregulated the transcription factor CASZ1, a positive regulator of p75NTR. CASZ1 knockdown attenuated VPA-induced p75NTR overexpression. Cell treatment with VPA favoured proNGF-induced p75NTR/sortilin interaction and the exposure to proNGF enhanced JNK activation and apoptotic cell death elicited by VPA. Depletion of p75NTR or addition of the sortilin agonist neurotensin to block proNGF/sortilin interaction reduced the apoptotic response to VPA and proNGF. Exposure of mouse cerebellar granule cells to VPA upregulated p75NTR and sortilin and induced apoptosis which was enhanced by proNGF. These results indicate that VPA upregulates p75NTR apoptotic cell signalling through an epigenetic mechanism involving HDAC inhibition and suggest that this effect may contribute to the anti-neuroblastoma and neurotoxic effects of VPA.

抗癫痫药和情绪稳定剂丙戊酸 (VPA) 已被证明可发挥抗肿瘤作用，并通过尚未完全了解的机制在发育中的大脑中引起神经元损伤。在本研究中，我们表明 SH-SY5Y 和 LAN-1 人神经母细胞瘤细胞长期暴露于临床相关浓度的 VPA 会显着诱导常见神经营养因子受体 p75NTR 及其共同受体分选蛋白的蛋白质和转录水平，两个细胞凋亡的启动子响应于原神经营养因子。VPA 对 p75NTR 和分拣蛋白的诱导与受体蛋白的质膜表达增加有关，并通过用几种组蛋白脱乙酰酶 (HDAC) 抑制剂进行细胞处理来模拟。VPA 和 HDAC1 敲低降低了 EZH2 的水平，多梳抑制复合物 2 的核心成分，并上调转录因子 CASZ1，这是 p75NTR 的正调节因子。CASZ1 敲低减弱了 VPA 诱导的 p75NTR 过表达。用 VPA 处理细胞有利于 proNGF 诱导的 p75NTR/sortilin 相互作用，暴露于 proNGF 增强了 VPA 引起的 JNK 激活和细胞凋亡。p75NTR 的消耗或添加分拣蛋白激动剂神经降压素以阻断 proNGF/分拣蛋白相互作用降低了对 VPA 和 proNGF 的细胞凋亡反应。将小鼠小脑颗粒细胞暴露于 VPA 上调 p75NTR 和分拣蛋白并诱导细胞凋亡，proNGF 增强了这种细胞凋亡。