苹果酸 - 天冬氨酸穿梭（Malate-aspartate shuttle，MAS）对于肿瘤的糖酵解和能量代谢至关重要，然而在儿童期最常见的颅外恶性肿瘤神经母细胞瘤（neuroblastoma，NB）中，其调控机制仍未被阐明。通过分析多组学数据，发现GATA结合蛋白2（GATA2）及其反义RNA 1（GATA2-AS1）在NB进展过程中抑制MAS。机制研究揭示，GATA2抑制了谷氨酸-草酰乙酸转氨酶2（glutamic-oxaloacetic transaminase 2，GOT2）和苹果酸脱氢酶2（malate dehydrogenase 2，MDH2）的转录。作为受RNA结合基序蛋白15介导的N6-甲基腺苷酸甲基化不稳定的长非编码RNA，GATA2-AS1与远上游元件结合蛋白3（far upstream element binding protein 3，FUBP3）结合，抑制其液-液相分离和与SUZ12（suppressor of zest 12）的相互作用，导致SUZ12的活性降低，从而使得GATA2和其他肿瘤抑制因子的上调发生于表观遗传学层面。营救实验揭示，GATA2-AS1通过抑制FUBP3与SUZ12之间的相互作用来抑制MAS和NB进展。临床前研究结果显示，携带GATA2-AS1的慢病毒抑制了NB异种移植瘤的MAS、厌氧酵解和侵袭行为。值得注意的是，低GATA2-AS1或GATA2表达和高FUBP3、SUZ12、GOT2或MDH2水平与NB患者不良预后有关。这些发现表明，GATA2-AS1通过调节SUZ12的活性来抑制FUBP3的液-液相分离，从而抑制MAS和NB的进展。© 2023年。作者，独家授权于施普林格自然有限公司。

Malate-aspartate shuttle (MAS) is essential for maintaining glycolysis and energy metabolism in tumors, while its regulatory mechanisms in neuroblastoma (NB), the commonest extracranial malignancy during childhood, still remain to be elucidated. Herein, by analyzing multi-omics data, GATA binding protein 2 (GATA2) and its antisense RNA 1 (GATA2-AS1) were identified to suppress MAS during NB progression. Mechanistic studies revealed that GATA2 inhibited the transcription of glutamic-oxaloacetic transaminase 2 (GOT2) and malate dehydrogenase 2 (MDH2). As a long non-coding RNA destabilized by RNA binding motif protein 15-mediated N6-methyladenosine methylation, GATA2-AS1 bound with far upstream element binding protein 3 (FUBP3) to repress its liquid-liquid phase separation and interaction with suppressor of zest 12 (SUZ12), resulting in decrease of SUZ12 activity and epigenetic up-regulation of GATA2 and other tumor suppressors. Rescue experiments revealed that GATA2-AS1 inhibited MAS and NB progression via repressing interaction between FUBP3 and SUZ12. Pre-clinically, administration of lentivirus carrying GATA2-AS1 suppressed MAS, aerobic glycolysis, and aggressive behaviors of NB xenografts. Notably, low GATA2-AS1 or GATA2 expression and high FUBP3, SUZ12, GOT2 or MDH2 levels were linked with unfavorable outcome of NB patients. These findings suggest that GATA2-AS1 inhibits FUBP3 phase separation to repress MAS and NB progression via modulating SUZ12 activity.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.