State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China.
Oncogene. 2017 Aug 17;36(33):4706-4718. doi: 10.1038/onc.2017.34. Epub 2017 Apr 10.
Polycomb group (PcG) proteins play an important role in development and stem cell maintenance, and their dysregulation have been closely linked to oncogenesis and cancer stem cell phenotypes. Here, we found that nervous system polycomb 1 (NSPc1) was highly expressed in stem cell-like glioma cells (SLCs). Knockdown of NSPc1 in SLCs resulted in impaired neurosphere formation and self-renewal abilities, down-regulated expression of stemness markers such as NESTIN, CD133 and SOX2, and decreased capacity to propagate subcutaneous xenografts. In contrast, glioma cells overexpressing NSPc1 exhibited a stem cell-like phenotype, up-regulated expression of stemness markers NESTIN, CD133 and SOX2, and an enhanced capacity to propagate subcutaneous xenografts. Furthermore, we identified that NSPc1 epigenetically repressed the expression of retinol dehydrogenase 16 (RDH16) by directly binding to a region upstream (-1073 to -823) of the RDH16 promoter. Next, we confirmed that RDH16 is a stemness suppressor that partially rescues SLCs from the NSPc1-induced increase in neurosphere formation. Finally, we showed that ATRA partly reversed the NSPc1-induced stemness enhancement in SLCs, through mechanisms correlated with an ATRA-dependent decrease in the expression of NSPc1. Thus, our results demonstrate that NSPc1 promotes cancer stem cell self-renewal by repressing the synthesis of ATRA via targeting RDH16 and may provide novel targets for glioma treatment in the future.
多梳抑制复合物（PcG）蛋白在发育和干细胞维持中发挥重要作用，其失调与肿瘤发生和癌症干细胞表型密切相关。在这里，我们发现神经系统多梳蛋白 1（NSPc1）在干细胞样神经胶质瘤细胞（SLCs）中高表达。NSPc1 在 SLCs 中的敲低导致神经球形成和自我更新能力受损，干细胞标志物如 NESTIN、CD133 和 SOX2 的表达下调，以及皮下异种移植的繁殖能力降低。相比之下，过表达 NSPc1 的神经胶质瘤细胞表现出干细胞样表型，干细胞标志物 NESTIN、CD133 和 SOX2 的表达上调，以及皮下异种移植的繁殖能力增强。此外，我们确定 NSPc1 通过直接结合 RDH16 启动子上游（-1073 至-823）的一个区域，表观遗传地下调视黄醇脱氢酶 16（RDH16）的表达。接下来，我们证实 RDH16 是一种干细胞抑制因子，可部分挽救 NSPc1 诱导的神经球形成增加。最后，我们表明 ATRA 通过与 ATRA 依赖性 NSPc1 表达降低相关的机制，部分逆转了 NSPc1 诱导的 SLCs 中的干细胞增强作用。因此，我们的结果表明，NSPc1 通过靶向 RDH16 抑制 ATRA 的合成来促进癌症干细胞自我更新，并可能为未来的胶质瘤治疗提供新的靶点。
