Glioma is the most common brain malignancy, characterized by high morbidity, high mortality, and treatment-resistance. Inverted CCAAT box Binding Protein of 90 kDa (ICBP90) has been reported to be involved in tumor progression and the maintenance of DNA methylation. Herein, we constructed ICBP90 over-expression and knockdown glioma cell lines, and found that ICBP90 knockdown inhibited glioma cell proliferation, migration, and invasion. ICBP90 silencing potentially enhanced cellular sensitivity to -platinum (DDP) and exacerbated DDP-induced pyroptosis, manifested by the elevated levels of gasdermin D-N-terminal and cleaved caspase 1; whereas, ICBP90 over-expression exhibited the opposite effects. Consistently, ICBP90 knockdown inhibited tumor growth in an mouse xenograft study using U251 cells stably expressing sh-ICBP90 and oe-ICBP90. Further experiments found that ICBP90 reduced the expression of Dickkopf 3 homolog (DKK3), a negative regulator of β-catenin, by binding its promoter and inducing DNA methylation. ICBP90 knockdown prevented the nuclear translocation of β‐catenin and suppressed the expression of c-Myc and cyclin D1. Besides, DKK3 over-expression restored the effects of ICBP90 over-expression on cell proliferation, migration, invasion, and DDP sensitivity. Our findings suggest that ICBP90 inhibits the expression of DKK3 in glioma by maintaining DKK3 promoter methylation, thereby conducing to ICBP90-mediated carcinogenesis and drug insensitivity.

中文翻译：

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ICBP90 是一种表观遗传调节因子，可诱导 DKK3 启动子甲基化，促进神经胶质瘤进展，并降低对顺铂的敏感性


胶质瘤是最常见的脑恶性肿瘤，具有高发病率、高死亡率和治疗耐药性的特点。据报道，90 kDa 的反向 CCAAT 盒结合蛋白 (ICBP90) 参与肿瘤进展和 DNA 甲基化的维持。在此，我们构建了ICBP90过表达和敲低的胶质瘤细胞系，发现ICBP90敲低抑制了胶质瘤细胞的增殖、迁移和侵袭。 ICBP90 沉默可能增强细胞对铂 (DDP) 的敏感性，并加剧 DDP 诱导的细胞焦亡，表现为gasdermin DN 末端和 cleaved caspase 1 水平升高；而ICBP90过表达则表现出相反的效果。一致地，在使用稳定表达 sh-ICBP90 和 oe-ICBP90 的 U251 细胞的小鼠异种移植研究中，ICBP90 敲低抑制了肿瘤生长。进一步的实验发现，ICBP90 通过结合其启动子并诱导 DNA 甲基化，降低了β-连环蛋白负调节因子 Dickkopf 3 同源物 (DKK3) 的表达。 ICBP90 敲低可阻止 β-catenin 的核转位并抑制 c-Myc 和细胞周期蛋白 D1 的表达。此外，DKK3过表达恢复了ICBP90过表达对细胞增殖、迁移、侵袭和DDP敏感性的影响。我们的研究结果表明，ICBP90 通过维持 DKK3 启动子甲基化来抑制神经胶质瘤中 DKK3 的表达，从而导致 ICBP90 介导的致癌作用和药物不敏感性。