Deubiquitinating enzyme USP33 restrains docetaxel-induced apoptosis via stabilising the phosphatase DUSP1 in prostate cancer
Deubiquitinating enzyme USP33 restrains docetaxel-induced apoptosis via stabilising the phosphatase DUSP1 in prostate cancer
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DOI：
10.1038/s41418-019-0473-8
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发表时间：
2020-06-01
影响因子：
12.4
通讯作者：
Sun, Yinghao
中科院分区：
文献类型：
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作者：
Guo, Fei;Zhang, Chao;Sun, Yinghao
去势抵抗性前列腺癌（CRPC）的治疗仍面临许多挑战。多西紫杉醇是CRPC患者常用的化疗药物。然而，以多西他赛为基础的化疗通常会导致多西他赛耐药，部分原因是由于CRPC细胞对多西他赛诱导的凋亡有耐药性。在这里，我们报道了去泛素化酶泛素特异性蛋白酶33 （USP33）抑制多西他赛诱导的前列腺癌细胞凋亡，包括雄激素非依赖性前列腺癌细胞。USP33在前列腺癌细胞和组织中过表达。我们发现，敲低或敲除USP33可增强多西他赛诱导的前列腺癌细胞凋亡，并伴随着cJUN nh2末端激酶（JNK）磷酸化的增加。在使用JNK抑制剂SP600125或靶向JNK的siRNA阻断多西他赛诱导的JNK激活后，USP33敲除增强的细胞凋亡被逆转。此外，我们发现USP33可以与磷酸酶DUSP1相互作用，负向调节JNK的激活，而USP33的敲低促进了DUSP1的蛋白酶体降解。在机制上，我们发现USP33可以抑制DUSP1的Lys48 (K48)-linked多泛素化。更重要的是，DUSP1过表达可以逆转USP33敲低诱导的多西他赛治疗前列腺癌细胞的JNK激活和凋亡。因此，USP33在前列腺癌中的过表达可能通过抑制其伴侣DUSP1的降解，导致JNK活化受损和细胞凋亡，从而促进多西紫杉醇耐药。我们的研究表明，USP33- dusp1 - jnk可能是介导CRPC多西他赛耐药的关键信号模块，表明USP33是CRPC潜在的新治疗靶点。
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.