Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado, Aurora, CO, USA.
Department of Internal Medicine, Division of Gastroenterology, Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, TX, USA.
Oncogene. 2021 Jan;40(2):369-383. doi: 10.1038/s41388-020-01538-y. Epub 2020 Nov 3.
The Wnt/β-catenin signaling pathway is aberrantly activated in the majority of colorectal cancer cases due to somatic mutations in the adenomatous polyposis coli (APC) gene. Prohibitin 1 (PHB1) serves pleiotropic cellular functions with dynamic subcellular trafficking, facilitating signaling crosstalk between organelles. Nuclear-localized PHB1 is an important regulator of gene transcription. Using mice with inducible intestinal epithelial cell (IEC)-specific deletion of Phb1 (Phb1) and mice with IEC-specific overexpression of Phb1 (Phb1Tg), we demonstrate that IEC-specific PHB1 combats intestinal tumorigenesis in the Apc mouse model by inhibiting Wnt/β-catenin signaling. Forced nuclear accumulation of PHB1 in human RKO or SW48 CRC cell lines increased AXIN1 expression and decreased cell viability. PHB1 deficiency in CRC cells decreased AXIN1 expression and increased β-catenin activation that was abolished by XAV939, a pharmacological AXIN stabilizer. These results define a role of PHB1 in inhibiting the Wnt/β-catenin pathway to influence the development of intestinal tumorigenesis. Induction of nuclear PHB1 trafficking provides a novel therapeutic option to influence AXIN1 expression and the β-catenin destruction complex in Wnt-driven intestinal tumorigenesis.
Wnt/β-catenin 信号通路在大多数结直肠癌病例中由于腺瘤性结肠息肉病（APC）基因的体细胞突变而异常激活。抑制素 1（PHB1）具有动态的亚细胞运输功能，发挥着多种细胞功能，促进细胞器之间的信号串扰。核定位的 PHB1 是基因转录的重要调节因子。利用上皮细胞（IEC）特异性缺失 Phb1（Phb1）的小鼠和 IEC 特异性过表达 Phb1（Phb1Tg）的小鼠，我们证明 IEC 特异性 PHB1 通过抑制 Wnt/β-catenin 信号通路来对抗 Apc 模型中的肠道肿瘤发生。在人 RKO 或 SW48 CRC 细胞系中强制核积累 PHB1 增加了 AXIN1 的表达并降低了细胞活力。CRC 细胞中 PHB1 的缺失降低了 AXIN1 的表达并增加了 β-catenin 的激活，而 XAV939（一种 AXIN 稳定剂）可消除这种激活。这些结果定义了 PHB1 在抑制 Wnt/β-catenin 通路以影响肠道肿瘤发生发展中的作用。诱导核 PHB1 运输为影响 Wnt 驱动的肠道肿瘤发生中的 AXIN1 表达和 β-catenin 破坏复合物提供了一种新的治疗选择。
