Aurora-A has attracted a great deal of interest as a potential therapeutic target for patients with CRC. However, the outcomes of inhibitors targeting Aurora-A are not as favorable as expected, and the basis behind the ineffectiveness remains unknown. Here, we found that signal transducer and activator of transcription 1 (STAT1) was highly expressed in colorectal cancer (CRC) xenograft mouse models that were resistant to alisertib, an Aurora-A inhibitor. Unexpectedly, we found that alisertib disrupted Aurora-A binding with ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1), leading to UHRF1 mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1), which in turn resulted in demethylation of CpG islands of STAT1 promoter and STAT1 overexpression. Simultaneous silencing Aurora-A and UHRF1 prevented STAT1 overexpression and effectively inhibited CRC growth. Hence, concomitant targeting Aurora-A and UHRF1 can be a promising therapeutic strategy for CRC.

中文翻译：

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同时沉默 Aurora-A 和 UHRF1 通过调节 DNMT1 和 STAT1 的表达来抑制结直肠癌细胞的生长。

Aurora-A 作为 CRC 患者的潜在治疗靶点引起了极大的兴趣。然而，针对 Aurora-A 的抑制剂的结果并不像预期的那么好，无效背后的原因仍然未知。在这里，我们发现信号转导和转录激活因子 1 (STAT1) 在对 Aurora-A 抑制剂 alisertib 具有抗性的结直肠癌 (CRC) 异种移植小鼠模型中高度表达。出乎意料的是，我们发现 alisertib 破坏了 Aurora-A 与泛素样与植物同源结构域和无名指结构域 1 (UHRF1) 的结合，导致 UHRF1 介导的 DNA 甲基转移酶 1 (DNMT1) 的泛素化和降解，进而导致 CpG 的去甲基化STAT1 启动子岛和 STAT1 过表达。同时沉默 Aurora-A 和 UHRF1 可防止 STAT1 过表达并有效抑制 CRC 生长。因此，同时靶向 Aurora-A 和 UHRF1 可能是一种有前途的 CRC 治疗策略。