FOXO3 regulates a common genomic program in aging and glioblastoma stem cells.
FOXO3 regulates a common genomic program in aging and glioblastoma stem cells.
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DOI：
10.1002/aac2.12043
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发表时间：
2021-12
期刊：
影响因子：
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通讯作者：
Webb, Ashley E
中科院分区：
文献类型：
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作者：
Audesse, Amanda J;Karashchuk, Galina;Gardell, Zachary A;Lakis, Nelli S;Maybury-Lewis, Sun Y;Brown, Abigail K;Leeman, Dena S;Teo, Yee Voan;Neretti, Nicola;Anthony, Douglas C;Brodsky, Alexander S;Webb, Ashley E
胶质母细胞瘤(GBM)是一种侵袭性的、与年龄相关的恶性胶质瘤，其中含有大量的癌症干细胞。这些胶质瘤干细胞(GSCs)由于其存在于缓慢循环的静止状态而逃避治疗干预并重新滋生肿瘤。虽然众所周知，衰老会增加癌症的发生，但支持GSC致瘤性的机制与生理衰老之间的关系仍不清楚。在这里，我们研究了促进健康衰老的转录调控因子Forkhead Box O_3(FOXO_3)影响GSC功能的转录机制，以及FOXO_3转录网络在衰老和GBM中调控失调的程度。我们对临床GBM肿瘤进行了转录组分析，观察到FOXO 3的高活性与干细胞静止、氧化代谢降低和改善患者预后的基因表达特征有关。与这些发现一致的是，我们发现FOXO_3活性的升高显著降低了GBM来源的GSCs的增殖。使用RNA-SEQ，我们发现在GSCs中功能性地消融FOXO_3重新连接了与新陈代谢、表观遗传稳定性、静止和分化相关的转录电路。由于FOX03与健康衰老有关，我们随后调查了它在多大程度上调节衰老的神经干细胞(NSCs)和GSCs的共同转录程序。我们发现了一个共同的转录程序，最引人注目的是，我们发现FOXO_3调节的通路与衰老和GBM中线粒体功能的改变有关。这项工作确定了FOXO相关的转录程序，它与GSCs和衰老的NSCs相关，并丰富了与GBM和衰老相关的代谢和茎干途径。
Glioblastoma (GBM) is an aggressive, age-associated malignant glioma that contains populations of cancer stem cells. These glioma stem cells (GSCs) evade therapeutic interventions and repopulate tumors due to their existence in a slowly cycling quiescent state. Although aging is well known to increase cancer initiation, the extent to which the mechanisms supporting GSC tumorigenicity are related to physiological aging remains unknown. Here, we investigate the transcriptional mechanisms by which Forkhead Box O3 (FOXO3), a transcriptional regulator that promotes healthy aging, affects GSC function and the extent to which FOXO3 transcriptional networks are dysregulated in aging and GBM. We performed transcriptome analysis of clinical GBM tumors and observed that high FOXO3 activity is associated with gene expression signatures of stem cell quiescence, reduced oxidative metabolism, and improved patient outcomes. Consistent with these findings, we show that elevated FOXO3 activity significantly reduces the proliferation of GBM-derived GSCs. Using RNA-seq, we find that functional ablation of FOXO3 in GSCs rewires the transcriptional circuitry associated with metabolism, epigenetic stability, quiescence, and differentiation. Since FOXO3 has been implicated in healthy aging, we then investigated the extent to which it regulates common transcriptional programs in aging neural stem cells (NSCs) and GSCs. We uncover a shared transcriptional program and, most strikingly, find that FOXO3-regulated pathways are associated with altered mitochondrial functions in both aging and GBM. This work identifies a FOXO-associated transcriptional program that correlates between GSCs and aging NSCs and is enriched for metabolic and stemness pathways connected with GBM and aging.