靶向 TRIM24 通过 LSD1/CoREST 复合物促进神经母细胞瘤分化并降低肿瘤发生能力。

Targeting TRIM24 promotes neuroblastoma differentiation and decreases tumorigenicity via LSD1/CoREST complex.

机构信息

Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University, Shanghai, 200127, China.

Pediatric Translational Medicine Institute, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai Jiao Tong University, Shanghai, 200127, China.

出版信息

Cell Oncol (Dordr). 2023 Dec;46(6):1763-1775. doi: 10.1007/s13402-023-00843-4. Epub 2023 Jul 19.

DOI:10.1007/s13402-023-00843-4

PMID:37466744

Abstract

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.

摘要

目的

高危神经母细胞瘤（NB）的预后仍然较差，诱导 NB 分化是临床治疗的一种潜在策略，但潜在机制仍不清楚。在这里，我们确定 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以确定 TRIM24 在 NB 中的作用。通过细胞形态、球体形成、软琼脂测定和裸鼠皮下异种移植来确定 TRIM24 对 NB 分化和生长的影响。使用 RNA-Seq 和 qRT-PCR 来鉴定涉及的基因和途径。使用质谱和共免疫沉淀来探索蛋白质的相互作用。

结果

Trim24 在 TH-MYCN 转基因小鼠和临床 NB 标本中的自发性 NB 中高度表达。它与 NB 分化不良和预后不良有关。神经母细胞瘤细胞中 TRIM24 的敲除促进细胞分化，降低细胞干性，并抑制软琼脂中的集落形成和裸鼠皮下异种移植肿瘤生长。在机制上，TRIM24 敲除通过抑制 LSD1/CoREST 复合物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 敲除激活了视黄酸途径。TRIM24 的靶向与视黄酸（RA）联合使用可协同促进 NB 细胞分化并抑制细胞活力。