Docetaxel is commonly used to treat hormone-refractory prostate cancer (HRPC), but its clinical efficacy is limited by drug resistance, with the molecular mechanisms remaining elusive. The E3 ubiquitin ligase EDD modifies substrate proteins through ubiquitination and is involved in the regulation of cell proliferation and tumorigenesis. However, its role in docetaxel resistance of prostate cancer is unknown. Here, we show that EDD is upregulated in docetaxel-resistant HRPC cells, as well as in human HRPC treated with docetaxel chemotherapy. Functionally, EDD knockdown resensitizes HRPC cells to docetaxel in vitro and in vivo, and in reverse, EDD overexpression promotes docetaxel resistance. We further show that the Wnt/β-Catenin signaling is activated in docetaxel-resistant HRPC cells, which can be promoted by EDD. Finally, inhibiting Wnt signaling through β-Catenin knockdown remarkably attenuates EDD-mediated docetaxel resistance, suggesting that the activated Wnt/β-Catenin signaling is a key contributor to EDD-conferred docetaxel resistance in HRPC cells. Altogether, our study uncovers a positive role of EDD in docetaxel resistance in prostate cancer, and further links it with the regulation of Wnt/β-Catenin signaling.
Keywords: Docetaxel resistance; E3 ubiquitin ligase; EDD; Prostate cancer; Wnt/β-Catenin signaling.
Copyright © 2019. Published by Elsevier Inc.