1Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha.
2NHC Key Laboratory of Carcinogenesis, Cancer Research Institute, Central South University, Changsha.
Neurosurg Focus. 2024 May;56(5):E17. doi: 10.3171/2024.2.FOCUS244.
There is a lack of effective drugs to treat the progression and recurrence of chordoma, which is widely resistant to treatment in chemotherapy. The authors investigated the functional and therapeutic relevance of the E1A-binding protein p300 (EP300) in chordoma.
The expression of EP300 and vimentin was examined in specimens from 9 patients with primary and recurrent chordoma with immunohistochemistry. The biological functions of EP300 were evaluated with Cell Counting Kit-8, clonogenic assays, and transwell assays. The effects of EP300 inhibitors (C646 and SGC-CBP30) on chordoma cell motility were assessed with these assays. The effect of the combination of EP300 inhibitors and cisplatin on chordoma cells was evaluated with clonogenic assays. Reverse transcription quantitative polymerase chain reaction and Western blot techniques were used to explore the potential mechanism of EP300 through upregulation of the expression of vimentin to promote the progression of chordoma.
Immunohistochemistry analysis revealed a positive correlation between elevated EP300 expression levels and recurrence. The upregulation of EP300 stimulated the growth of and increased the migratory and invasive capabilities of chordoma cells, along with upregulating vimentin expression and consequently impacting their invasive properties. Conversely, EP300 inhibitors decreased cell proliferation and downregulated vimentin. Furthermore, the combination of EP300 inhibition and cisplatin exhibited an enhanced anticancer effect on chordoma cells, indicating that EP300 may influence chordoma sensitivity to chemotherapy.
These findings indicate that EP300 functions as an oncogene in chordoma. Targeting EP300 offers a novel approach to the development and clinical treatment of chordoma.
目前缺乏有效药物治疗 chordoma 的进展和复发，该疾病对化疗广泛耐药。作者研究了 E1A 结合蛋白 p300（EP300）在 chordoma 中的功能和治疗相关性。
采用免疫组织化学方法检测 9 例原发性和复发性 chordoma 标本中 EP300 和波形蛋白的表达。通过细胞计数试剂盒-8、集落形成实验和 Transwell 实验评估 EP300 的生物学功能。采用这些实验评估 EP300 抑制剂（C646 和 SGC-CBP30）对 chordoma 细胞迁移的影响。采用集落形成实验评估 EP300 抑制剂与顺铂联合对 chordoma 细胞的影响。采用逆转录定量聚合酶链反应和 Western blot 技术，通过上调波形蛋白的表达来探索 EP300 促进 chordoma 进展的潜在机制。
免疫组织化学分析显示 EP300 表达水平升高与复发呈正相关。EP300 的上调刺激 chordoma 细胞的生长，并增加其迁移和侵袭能力，同时上调波形蛋白的表达，从而影响其侵袭特性。相反，EP300 抑制剂降低细胞增殖并下调波形蛋白。此外，EP300 抑制联合顺铂对 chordoma 细胞表现出增强的抗癌作用，表明 EP300 可能影响 chordoma 对化疗的敏感性。
这些发现表明 EP300 在 chordoma 中起癌基因作用。靶向 EP300 为 chordoma 的开发和临床治疗提供了一种新方法。
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