Therapeutic Targeting of MZF1-AS1/PARP1/E2F1 Axis Inhibits Proline Synthesis and Neuroblastoma Progression
Therapeutic Targeting of MZF1-AS1/PARP1/E2F1 Axis Inhibits Proline Synthesis and Neuroblastoma Progression
复制标题
MZF1-AS1/PARP1/E2F1 轴的治疗靶向抑制脯氨酸合成和神经母细胞瘤进展
DOI：
10.1002/advs.201900581
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发表时间：
2019-08-10
期刊：
影响因子：
15.1
通讯作者：
Tong, Qiangsong
中科院分区：
文献类型：
--
作者：
Fang, Erhu;Wang, Xiaojing;Tong, Qiangsong
脯氨酸合成在促进肿瘤进展的代谢重编程中起重要作用。然而，脯氨酸合成基因在神经母细胞瘤（NB）中的表达调控机制仍不清楚。在此，通过对公共数据集的综合筛选和氨基酸谱分析，髓样锌指1（MZF 1）和MZF 1反义RNA 1（MZF 1-AS 1）被鉴定为脯氨酸合成和NB进展的转录调节因子。机制上，转录因子MZF 1促进醛脱氢酶18家族成员A1和吡咯啉-5-羧酸还原酶1的表达，而脯氨酸促进NB细胞的侵袭性。此外，MZF 1-AS 1结合聚（ADP-核糖）聚合酶1（PARP 1），以促进其与E2 F转录因子1（E2 F1）的相互作用，导致E2 F1的反式激活和MZF 1和其他与肿瘤进展相关的致癌基因的上调。施用阻断MZF 1-AS 1-PARP 1相互作用的小肽或靶向MZF 1-AS 1的慢病毒介导的短发夹RNA抑制NB细胞的脯氨酸合成、肿瘤发生和侵袭性。在临床NB病例中，MZF 1-AS 1、PARP 1、E2 F1或MZF 1的高表达与患者的不良存活相关。这些结果表明，MZF 1-AS 1/PARP 1/E2 F1轴的治疗靶向抑制脯氨酸合成和NB进展。
Proline synthesis plays an important role in the metabolic reprogramming that contributes to tumor progression. However, the mechanisms regulating expression of proline synthetic genes in neuroblastoma (NB) remain elusive. Herein, through integrative screening of a public dataset and amino acid profiling analysis, myeloid zinc finger 1 (MZF1) and MZF1 antisense RNA 1 (MZF1-AS1) are identified as transcriptional regulators of proline synthesis and NB progression. Mechanistically, transcription factor MZF1 promotes the expression of aldehyde dehydrogenase 18 family member A1 and pyrroline-5-carboxylate reductase 1, while proline facilitates the aggressiveness of NB cells. In addition, MZF1-AS1 binds poly(ADP-ribose) polymerase 1 (PARP1) to facilitate its interaction with E2F transcription factor 1 (E2F1), resulting in transactivation of E2F1 and upregulation of MZF1 and other oncogenic genes associated with tumor progression. Administration of a small peptide blocking MZF1-AS1-PARP1 interaction or lentivirus-mediated short hairpin RNA targeting MZF1-AS1 suppresses the proline synthesis, tumorigenesis, and aggressiveness of NB cells. In clinical NB cases, high expression of MZF1-AS1, PARP1, E2F1, or MZF1 is associated with poor survival of patients. These results indicate that therapeutic targeting of MZF1-AS1/PARP1/E2F1 axis inhibits proline synthesis and NB progression.