p53 is an intensely studied tumor-suppressive transcription factor. Recent studies suggest that the RNA-binding protein (RBP) ZMAT3 is important in mediating the tumor-suppressive effects of p53. Here, we globally identify ZMAT3-regulated RNAs and their binding sites at nucleotide resolution in intact colorectal cancer (CRC) cells. ZMAT3 binds to thousands of mRNA precursors, mainly at intronic uridine-rich sequences and affects their splicing. The strongest alternatively spliced ZMAT3 target was CD44, a cell adhesion gene and stem cell marker that controls tumorigenesis. Silencing ZMAT3 increased inclusion of CD44 variant exons, resulting in significant up-regulation of oncogenic CD44 isoforms (CD44v) and increased CRC cell growth that was rescued by concurrent knockdown of CD44v. Silencing p53 phenocopied the loss of ZMAT3 with respect to CD44 alternative splicing, suggesting that ZMAT3-mediated regulation of CD44 splicing is vital for p53 function. Collectively, our findings uncover a p53–ZMAT3–CD44 axis in growth suppression in CRC cells.

中文翻译：

---

p53 诱导的 RNA 结合蛋白 ZMAT3 是一种剪接调节因子，可抑制结直肠癌中致癌 CD44 变体的剪接

p53 是一种经过深入研究的肿瘤抑制转录因子。最近的研究表明，RNA 结合蛋白 (RBP) ZMAT3 在介导 p53 的肿瘤抑制作用中发挥着重要作用。在这里，我们在完整结直肠癌 (CRC) 细胞中以核苷酸分辨率全面鉴定了 ZMAT3 调节的 RNA 及其结合位点。ZMAT3 与数千个 mRNA 前体结合，主要是在内含子富含尿苷的序列上，并影响它们的剪接。最强的选择性剪接 ZMAT3 靶点是CD44，它是一种控制肿瘤发生的细胞粘附基因和干细胞标记物。沉默 ZMAT3 增加了CD44变异外显子的包含，导致致癌CD44同工型 ( CD44v )显着上调，并增加了 CRC 细胞的生长，这是通过同时敲低CD44v来挽救的。沉默 p53 表现出 ZMAT3 相对于CD44选择性剪接的损失，表明 ZMAT3 介导的CD44剪接调节对于 p53 功能至关重要。总的来说，我们的研究结果揭示了 p53-ZMAT3-CD44 轴在 CRC 细胞生长抑制中的作用。