靶向TRIM24可通过LSD1/CoREST复合物促进神经母细胞瘤分化并降低致瘤性。

IF 4.9 2区 医学 Q2 CELL BIOLOGY Cellular Oncology Pub Date : 2023-12-01 Epub Date: 2023-07-19 DOI:10.1007/s13402-023-00843-4
Qiqi Shi, Bo Yu, Yingwen Zhang, Yi Yang, Chenxin Xu, Mingda Zhang, Guoyu Chen, Fei Luo, Bowen Sun, Ru Yang, Yanxin Li, Haizhong Feng
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引用次数: 0

摘要

目的:高危神经母细胞瘤(NB)预后不良,诱导NB分化是临床治疗的一种潜在策略,但其机制尚不明确。在这里,我们发现TRIM24是NB分化的重要调节因子。方法:分析多个数据集和临床标本,确定TRIM24在NB中的作用。通过裸鼠细胞形态、球形成、软琼脂实验和皮下移植观察TRIM24对NB分化和生长的影响。采用RNA-Seq和qRT-PCR鉴定相关基因和通路。采用质谱法和免疫共沉淀法研究蛋白间的相互作用。结果:在TH-MYCN转基因小鼠和临床NB标本中,Trim24在自发性NB中高表达。它与NB分化差和预后不良有关。敲除神经母细胞瘤细胞中的TRIM24可促进细胞分化,降低细胞干性,抑制裸小鼠软琼脂和皮下异种移植物肿瘤生长中的集落形成。从机制上讲,敲除TRIM24通过抑制LSD1/CoREST复合体的形成来改变与神经分化和发育相关的基因和途径。此外,TRIM24敲除激活维甲酸途径。靶向TRIM24与维甲酸(RA)联合可协同促进NB细胞分化并抑制细胞活力。结论:我们的研究结果表明TRIM24对NB分化至关重要,提示TRIM24联合RA在NB分化治疗中是一个有希望的治疗靶点。
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Targeting TRIM24 promotes neuroblastoma differentiation and decreases tumorigenicity via LSD1/CoREST complex.

Purpose: High-risk neuroblastoma (NB) still has an unfavorable prognosis and inducing NB differentiation is a potential strategy in clinical treatment, yet underlying mechanisms are still elusive. Here we identify TRIM24 as an important regulator of NB differentiation.

Methods: Multiple datasets and clinical specimens were analyzed to define the role of TRIM24 in NB. The effects of TRIM24 on differentiation and growth of NB were determined by cell morphology, spheres formation, soft agar assay, and subcutaneous xenograft in nude mice. RNA-Seq and qRT-PCR were used to identify genes and pathways involved. Mass spectrometry and co-immunoprecipitation were used to explore the interaction of proteins.

Results: Trim24 is highly expressed in spontaneous NB in TH-MYCN transgenic mice and clinical NB specimens. It is associated with poor NB differentiation and unfavorable prognostic. Knockout of TRIM24 in neuroblastoma cells promotes cell differentiation, reduces cell stemness, and inhibits colony formation in soft agar and subcutaneous xenograft tumor growth in nude mice. Mechanistically, TRIM24 knockout alters genes and pathways related to neural differentiation and development by suppressing LSD1/CoREST complex formation. Besides, TRIM24 knockout activates the retinoic acid pathway. Targeting TRIM24 in combination with retinoic acid (RA) synergistically promotes NB cell differentiation and inhibits cell viability.

Conclusion: Our findings demonstrate that TRIM24 is critical for NB differentiation and suggest that TRIM24 is a promising therapeutic target in combination with RA in NB differentiation therapy.

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来源期刊
Cellular Oncology
Cellular Oncology ONCOLOGY-CELL BIOLOGY
CiteScore
10.30
自引率
1.50%
发文量
86
审稿时长
12 months
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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