Abstract：
Zinc Finger MYND (Myeloid, Nervy, and DEAF-1) type containing 8 (ZMYND8) is a crucial epigenetic regulator that plays a multifaceted role in governing a spectrum of vital cellular processes, encompassing proliferation, apoptosis, migration, tumor suppression, and differentiation. It has emerged as a key player in neuronal differentiation by orchestrating the expression of neuronal lineage-committed genes. The present study uncovers the role of ZMYND8 in regulating the Sonic Hedgehog (SHH) signaling axis, which is crucial for neuronal differentiation. Genetic deletion of ZMYND8 leads to a significant reduction in SHH pathway genes, GLI1, and PTCH1 expression during all-trans-retinoic acid (ATRA)-induced differentiation. ZMYND8 and RNA pol II S5P are found to co-occupy the GLI1 and PTCH1 gene promoters, positively impacting their gene transcription upon ATRA treatment. Interestingly, ZMYND8 is found to counteract the inhibitory effects of Cyclopamine that block the upstream SHH pathway protein SMO, resulting in enhanced neurite formation in neuroblastoma cells following their treatment with ATRA. These results indicate that ZMYND8 is an epigenetic regulator of the SHH signaling pathway and has tremendous therapeutic potential in ATRA-mediated differentiation of neuroblastoma.
摘要：
锌指MYND（髓样，紧张,和DEAF-1）类型包含8（ZMYND8）是一种关键的表观遗传调节因子，在控制一系列重要的细胞过程中起着多方面的作用，包括扩散，凋亡，迁移,肿瘤抑制，和差异化。通过协调神经元谱系定向基因的表达，它已成为神经元分化的关键参与者。本研究揭示了ZMYND8在调节SonicHedgehog（SHH）信号轴，这对神经元分化至关重要。ZMYND8基因缺失导致SHH通路基因显著减少,GLI1和PTCH1在全反式维甲酸（ATRA）诱导的分化过程中的表达。发现ZMYND8和RNApolIIS5P共占据GLI1和PTCH1基因启动子，对ATRA治疗的基因转录产生积极影响。有趣的是,发现ZMYND8可以抵消环帕胺的抑制作用，该抑制作用阻断上游SHH途径蛋白SMO，在用ATRA治疗后，导致神经母细胞瘤细胞中神经突形成增强。这些结果表明，ZMYND8是SHH信号通路的表观遗传调节因子，在ATRA介导的神经母细胞瘤分化中具有巨大的治疗潜力。
