Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan.
Bachelor Program of Biotechnology, National Chung Hsing University, Taichung 40227, Taiwan.
Biochim Biophys Acta Mol Cell Res. 2019 Dec;1866(12):118537. doi: 10.1016/j.bbamcr.2019.118537. Epub 2019 Sep 2.
The epithelial-mesenchymal transition is a major cause of cancer metastasis, and deregulation of the transcription factor, Twist1, is a critical molecular event in the epithelial-mesenchymal transition. The importance of Twist1 protein turnover in this process has not yet been defined. Here, we show that HR23A directly targets the Twist1 protein without changing its gene transcription. Our experiments reveal that: HR23A interacts with Twist1, and this promotes the ubiquitin-mediated proteasomal degradation of Twist1. Depletion of HR23A enhances Twist1 protein levels, epithelial-mesenchymal transition, cancer cell migration and various cancer stemness properties, including the expression of major pluripotency factors, the capacity for tumor-sphere formation in culture and the expression of cancer stem cell surface markers. The increases of these stemness properties are reversed by ectopic expression of HR23A or further knockdown of Twist1 in HR23A-depleted cells. Thus, HR23A-knockdown cells appear to undergo epithelial-mesenchymal transition and take on certain attributes of cancer stemness. Together, our findings indicate that HR23A importantly contributes to regulating Twist1 protein stability, and suggest that altering the stability of Twist1 by modulating HR23A may be a new avenue for therapeutic intervention in cancer.
上皮-间充质转化是癌症转移的主要原因，转录因子 Twist1 的失调是上皮-间充质转化中的一个关键分子事件。在这个过程中，Twist1 蛋白周转的重要性尚未确定。在这里，我们表明 HR23A 直接靶向 Twist1 蛋白，而不改变其基因转录。我们的实验揭示了：HR23A 与 Twist1 相互作用，这促进了 Twist1 的泛素介导的蛋白酶体降解。HR23A 的耗竭增加了 Twist1 蛋白水平、上皮-间充质转化、癌细胞迁移和各种癌症干性特性，包括主要多能性因子的表达、在培养中肿瘤球体形成的能力以及癌症干细胞表面标志物的表达。这些干性特性的增加可被 HR23A 的异位表达或在 HR23A 耗竭细胞中进一步敲低 Twist1 逆转。因此，HR23A 敲低细胞似乎经历上皮-间充质转化并具有某些癌症干性特性。总之，我们的研究结果表明，HR23A 重要地有助于调节 Twist1 蛋白稳定性，并表明通过调节 HR23A 改变 Twist1 的稳定性可能是癌症治疗干预的新途径。
