Targeting TRIM24 promotes neuroblastoma differentiation and decreases tumorigenicity via LSD1/CoREST complex
Targeting TRIM24 promotes neuroblastoma differentiation and decreases tumorigenicity via LSD1/CoREST complex
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DOI：
10.1007/s13402-023-00843-4
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发表时间：
2023-07
影响因子：
6.6
通讯作者：
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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文献类型：
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作者：
Qiqi Shi;Bo Yu;Yingwen Zhang;Yi Yang;Chenxin Xu;Mingda Zhang;Guoyu Chen;Fei Luo;Bowen Sun;Ru Yang;Yanxin Li;Haizhong Feng
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，但其潜在机制尚不清楚。在这里，我们认为TRIM24是NB分化的重要调节因子。方法通过分析大量的数据集和临床标本来确定TRIM24在NB中的作用。通过细胞形态、球体形成、软琼脂实验和裸鼠皮下移植等方法观察TRIM24对NB细胞分化和生长的影响。用RNA-Seq和qRT-PCR方法鉴定相关基因和途径。结果在TH-MYCN转基因小鼠和临床神经母细胞瘤标本中，Trim24在自发性神经母细胞瘤中高表达。它与NB分化差和预后不良有关。在神经母细胞瘤细胞中敲除TRIM24促进细胞分化，降低细胞干性，并抑制软琼脂和裸鼠皮下移植瘤的集落形成。从机制上讲，TRIM24基因敲除通过抑制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基因敲除可激活维甲酸途径。靶向TRIM24联合维甲酸(RA)可协同促进NB细胞分化，抑制细胞活性。结论TRIM24在NB分化中起关键作用，提示TRIM24联合RA是NB分化治疗中有前景的治疗靶点。
PurposeHigh-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.MethodsMultiple 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.ResultsTrim24 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.ConclusionOur 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.