Deubiquitinating enzyme USP33 restrains docetaxel-induced apoptosis via stabilising the phosphatase DUSP1 in prostate cancer

The treatment of castration-resistant prostate Cancer (CRPC) still faces many challenges. Docetaxel is a chemotherapeutic drug commonly used in CRPC patients. However, docetaxel-based chemotherapy usually causes docetaxel resistance, partially due to the resistance of CRPC cells to docetaxel-induced Apoptosis. Here, we report that the deubiquitinating enzyme Ubiquitin-Specific Protease 33 (USP33) inhibits docetaxel-induced Apoptosis of prostate Cancer cells, including androgen-independent prostate Cancer cells. USP33 is overexpressed in prostate Cancer cells and tissues. We found that knockdown or knockout of USP33 enhanced docetaxel-induced Apoptosis of prostate Cancer cells, accompanied by increased phosphorylation of the cJUN NH2-terminal kinase (JNK). After blocking docetaxel-induced JNK activation using the JNK Inhibitor SP600125 or siRNA targeting JNK, the USP33 knockout-enhanced Apoptosis was reversed. Furthermore, we found that USP33 could interact with the Phosphatase DUSP1 to negatively regulate the activation of JNK, while USP33 knockdown promoted the proteasomal degradation of DUSP1. Mechanistically, we found that USP33 could inhibit the Lys48 (K48)-linked polyubiquitination of DUSP1. More importantly, DUSP1 overexpression could reverse the USP33 knockdown-induced JNK activation and Apoptosis in docetaxel-treated prostate Cancer cells. Therefore, USP33 overexpression in prostate Cancer may contribute to docetaxel resistance by inhibiting the degradation of its partner DUSP1, leading to impaired JNK activation and Apoptosis. Our study suggests that USP33-DUSP1-JNK may be a key signalling module mediating the docetaxel resistance of CRPC, indicating that USP33 is a potential novel therapeutic target in CRPC.