Although a growing body of evidence indicates that phenotypic plasticity exhibited by glioblastoma cells plays a central role in tumor development and post-therapy recurrence, the master drivers of their aggressiveness remain elusive. Here we mapped the changes in active (H3K4me3) and repressive (H3K27me3) histone modifications accompanying the repression of glioblastoma stem-like cells tumorigenicity. Genes with changing histone marks delineated a network of transcription factors related to cancerous behavior, stem state, and neural development, highlighting a previously unsuspected association between repression of ARNT2 and loss of cell tumorigenicity. Immunohistochemistry confirmed ARNT2 expression in cell sub-populations within proliferative zones of patients’ glioblastoma. Decreased ARNT2 expression was consistently observed in non-tumorigenic glioblastoma cells, compared to tumorigenic cells. Moreover, ARNT2 expression correlated with a tumorigenic molecular signature at both the tissue level within the tumor core and at the single cell level in the patients’ tumors. We found that ARNT2 knockdown decreased the expression of SOX9, POU3F2 and OLIG2, transcription factors implicated in glioblastoma cell tumorigenicity, and repressed glioblastoma stem-like cell tumorigenic properties in vivo. Our results reveal ARNT2 as a pivotal component of the glioblastoma cell tumorigenic signature, located at a node of a transcription factor network controlling glioblastoma cell aggressiveness.

尽管越来越多的证据表明，胶质母细胞瘤细胞表现出的表型可塑性在肿瘤的发展和治疗后的复发中起着核心作用，但其侵略性的主要驱动力仍然难以捉摸。在这里，我们绘制了伴随胶质母细胞瘤干样细胞致瘤性抑制的活性（H3K4me3）和抑制性（H3K27me3）组蛋白修饰的变化。组蛋白标记改变的基因描绘了与癌症行为，茎状态和神经发育相关的转录因子网络，突显了先前对ARNT2抑制之间未曾怀疑的关联和细胞致瘤性的丧失。免疫组织化学证实了ARNT2在患者胶质母细胞瘤增殖区内的细胞亚群中表达。与致瘤细胞相比，在非致瘤性胶质母细胞瘤细胞中始终观察到ARNT2表达降低。而且，ARNT2表达在肿瘤核心内的组织水平和患者肿瘤中的单细胞水平上均与致瘤分子特征相关。我们发现ARNT2组合式降低了SOX9，POU3F2和OLIG2的表达，与胶质母细胞瘤细胞致瘤性有关的转录因子，并抑制了胶质母细胞瘤干样细胞的致瘤特性。我们的结果表明ARNT2是胶质母细胞瘤细胞致瘤特征的关键组成部分，位于控制胶质母细胞瘤细胞侵袭性的转录因子网络的节点上。