p113 isoform encoded by CUX1 circular RNA drives tumor progression via facilitating ZRF1/BRD4 transactivation.
p113 isoform encoded by CUX1 circular RNA drives tumor progression via facilitating ZRF1/BRD4 transactivation.
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CUX1 环状 RNA 编码的 p113 亚型通过促进 ZRF1/BRD4 反式激活驱动肿瘤进展
DOI：
10.1186/s12943-021-01421-8
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发表时间：
2021-09-27
期刊：
影响因子：
37.3
通讯作者：
Tong Q
中科院分区：
文献类型：
--
作者：
Yang F;Hu A;Guo Y;Wang J;Li D;Wang X;Jin S;Yuan B;Cai S;Zhou Y;Li Q;Chen G;Gao H;Zheng L;Tong Q
神经母细胞瘤（NB）是儿童期最常见的颅外恶性肿瘤，其代谢重编程维持肿瘤发生和侵袭性，而其潜在机制和治疗方法仍然难以捉摸。通过桑格测序验证环状RNA（circRNA）。应用免疫共沉淀、质谱、染色质免疫沉淀（ChIP）测序和RNA测序分析来探索蛋白质相互作用和靶基因。通过ChIP、双荧光素酶报告基因、实时定量RT-PCR和蛋白质印迹分析观察基因表达调控。进行功能获得和丧失研究以观察circRNA编码的蛋白及其配偶体对NB细胞的脂质代谢、线粒体活性、生长、侵袭和转移的影响。在血清剥夺处理的NB细胞中鉴定了一种新的CUT样同源框1（CUX 1）的113个氨基酸的蛋白（p113）。进一步的验证性研究表明，核p113由CUX 1的circRNA编码，并促进NB细胞的脂质代谢重编程、线粒体活性、增殖、侵袭和转移。机制上，p113与Zuotin相关因子1（ZRF 1）和溴结构域蛋白4（BRD 4）相互作用形成转录调节复合物，并介导ZRF 1/BRD 4的反式激活，上调ALDH 3A 1、NDUFA 1和NDUFAF 5，这些对于脂肪醛转化为脂肪酸、脂肪酸β-氧化和线粒体复合物I活性至关重要。施用阻断p113-ZRF 1相互作用的抑制肽抑制NB细胞的肿瘤发生和侵袭性。在临床NB病例中，p113、ZRF 1或BRD 4的高表达与患者的生存率差相关。这些结果表明，由CUX 1环状RNA编码的p113亚型通过促进ZRF 1/BRD 4反式激活来驱动肿瘤进展。在线版本包含补充材料，可通过10.1186/s12943-021-01421-8获得。
Metabolic reprogramming sustains tumorigenesis and aggressiveness of neuroblastoma (NB), the most common extracranial malignancy in childhood, while underlying mechanisms and therapeutic approaches still remain elusive. Circular RNAs (circRNAs) were validated by Sanger sequencing. Co-immunoprecipitation, mass spectrometry, chromatin immunoprecipitation (ChIP) sequencing, and RNA sequencing assays were applied to explore protein interaction and target genes. Gene expression regulation was observed by ChIP, dual-luciferase reporter, real-time quantitative RT-PCR, and western blot assays. Gain- and loss-of-function studies were performed to observe the impacts of circRNA-encoded protein and its partners on the lipid metabolism, mitochondrial activity, growth, invasion, and metastasis of NB cells. A novel 113-amino acid protein (p113) of CUT-like homeobox 1 (CUX1) was identified in NB cells treated by serum deprivation. Further validating studies revealed that nuclear p113 was encoded by circRNA of CUX1, and promoted the lipid metabolic reprogramming, mitochondrial activity, proliferation, invasion, and metastasis of NB cells. Mechanistically, p113 interacted with Zuotin-related factor 1 (ZRF1) and bromodomain protein 4 (BRD4) to form a transcriptional regulatory complex, and mediated the transactivation of ZRF1/BRD4 in upregulating ALDH3A1, NDUFA1, and NDUFAF5 essential for conversion of fatty aldehydes into fatty acids, fatty acid β-oxidation, and mitochondrial complex I activity. Administration of an inhibitory peptide blocking p113-ZRF1 interaction suppressed the tumorigenesis and aggressiveness of NB cells. In clinical NB cases, high expression of p113, ZRF1, or BRD4 was associated with poor survival of patients. These results indicate that p113 isoform encoded by CUX1 circular RNA drives tumor progression via facilitating ZRF1/BRD4 transactivation. The online version contains supplementary material available at 10.1186/s12943-021-01421-8.
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影响因子：
37.3
作者：
Donati B;Lorenzini E;Ciarrocchi A
通讯作者：
Ciarrocchi A
影响因子：
9.7
作者：
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影响因子：
37.3
作者：
Li D;Mei H;Pu J;Xiang X;Zhao X;Qu H;Huang K;Zheng L;Tong Q
通讯作者：
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影响因子：
3.3
作者：
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通讯作者：
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影响因子：
5.8
作者：
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通讯作者：
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