Prostate Cancer Research Laboratory, Department of Urology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
The Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Prostate. 2019 Mar;79(4):403-413. doi: 10.1002/pros.23746. Epub 2018 Nov 28.
The substantial availability of hypoxia-inducible factor 1 (HIF-1) for pathophysiological states, such as malignancies and ischemia, is primarily regulated post-translationally through the ubiquitin proteolytic system. The balance between degradation and stabilization of HIF-1α protein is determined by specific E3 ligases. In our search for new E3 ligases that might affect HIF-1α protein expression, we studied the effects of beta-transducin repeat-containing protein (β-TrCP) on the hypoxic pathway in cancer cells. β-TrCP is overexpressed in many tumors and regulates various cellular processes through mediating the degradation of important targets. Unexpectedly, we found that β-TrCP overexpression increases HIF-1α protein expression level as well as HIF-1 transcriptional activity by stabilizing HIF-1α protein and preventing its ubiquitination and proteasomal degradation in prostate cancer cells. By using a proteomic approach, we succeeded in demonstrating that β-TrCP interferes with the association between HIF-1α and HSP70/CHIP, a HIF-1α established E3 ligase complex. Whereas the E3 ligase activity of β-TrCP is well known, antagonizing another E3 ligase is a new mechanism of action of this important E3. We suggest that destroying or suppressing β-TrCP and thereby interrupting the HIF-1 pathway, could be valuable antitumor therapy.
缺氧诱导因子 1（HIF-1）在病理学状态下（如恶性肿瘤和缺血）大量存在，其主要通过泛素蛋白酶体系统进行翻译后调节。HIF-1α 蛋白的降解和稳定之间的平衡由特定的 E3 连接酶决定。在寻找可能影响 HIF-1α 蛋白表达的新 E3 连接酶的过程中，我们研究了β-转导素重复蛋白（β-TrCP）对癌细胞中低氧途径的影响。β-TrCP 在许多肿瘤中过度表达，并通过介导重要靶标的降解来调节各种细胞过程。出乎意料的是，我们发现β-TrCP 过表达通过稳定 HIF-1α 蛋白并防止其泛素化和蛋白酶体降解，增加前列腺癌细胞中 HIF-1α 蛋白表达水平和 HIF-1 转录活性。通过使用蛋白质组学方法，我们成功地证明了β-TrCP 干扰 HIF-1α 与 HSP70/CHIP 之间的相互作用，HSP70/CHIP 是 HIF-1α 建立的 E3 连接酶复合物。虽然β-TrCP 的 E3 连接酶活性是众所周知的，但拮抗另一个 E3 连接酶是这种重要 E3 的一种新作用机制。我们认为，破坏或抑制β-TrCP 并因此中断 HIF-1 途径，可能是一种有价值的抗肿瘤治疗方法。
