Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China.
Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, Shanghai, 200092, China.
Oncogene. 2020 May;39(21):4212-4226. doi: 10.1038/s41388-020-1268-6. Epub 2020 Apr 6.
Impaired neuronal differentiation is a feature of neuroblastoma tumorigenesis, and the differentiation grade of neuroblastoma tumors is associated with patient prognosis. Detailed understanding of the molecular mechanisms underlying neuroblastoma differentiation will facilitate the development of effective treatment strategies. Recent studies have shown that myelin transcription factor 1 (MYT1) promotes vertebrate neurogenesis by regulating gene expression. We performed quantitative analysis of neuroblastoma samples, which revealed that MYT1 was differentially expressed among neuroblastoma patients with different pathological diagnoses. Analysis of clinical data showed that MYT1 overexpression was associated with a significantly shorter 3-year overall survival rate and poor differentiation in neuroblastoma specimens. MYT1 knockdown inhibited proliferation and promoted the expression of multiple differentiation-associated proteins. Integrated omics data indicated that many genes involved in neuro-differentiation were regulated by MYT1. Interestingly, many of these genes are targets of the REST complex; therefore, we further identified the physical interaction of MYT1 with LSD1/CoREST. Depletion of LSD1 or inhibition of LSD1 by ORY-1001 decreased MYT1 expression, providing an alternative approach to target MYT1. Taken together, our results indicate that MYT1 significantly attenuates cell differentiation by interacting with the LSD1/CoREST complex. MYT1 is, therefore, a promising therapeutic target for enhancing the neurite-inducing effect of retinoic acid and for inhibiting the growth of neuroblastoma.
神经元分化受损是神经母细胞瘤发生的一个特征，神经母细胞瘤肿瘤的分化程度与患者的预后相关。详细了解神经母细胞瘤分化的分子机制将有助于开发有效的治疗策略。最近的研究表明，少突胶质细胞转录因子 1（MYT1）通过调节基因表达促进脊椎动物神经发生。我们对神经母细胞瘤样本进行了定量分析，结果表明 MYT1 在具有不同病理诊断的神经母细胞瘤患者中存在差异表达。临床数据分析表明，MYT1 过表达与神经母细胞瘤标本中 3 年总生存率显著缩短和分化不良相关。MYT1 敲低抑制增殖并促进多种分化相关蛋白的表达。综合组学数据表明，许多参与神经分化的基因受 MYT1 调节。有趣的是，这些基因中的许多是 REST 复合物的靶标；因此，我们进一步确定了 MYT1 与 LSD1/CoREST 的物理相互作用。LSD1 的耗竭或 LSD1 抑制剂 ORY-1001 降低了 MYT1 的表达，为靶向 MYT1 提供了一种替代方法。总之，我们的研究结果表明，MYT1 通过与 LSD1/CoREST 复合物相互作用显著减弱细胞分化。因此，MYT1 是增强维甲酸诱导神经突生长和抑制神经母细胞瘤生长的有前途的治疗靶点。
