Inhibition of the deubiquitinase USP9x induces pre-B cell homeobox 1 (PBX1) degradation and thereby stimulates prostate cancer cell apoptosis
Inhibition of the deubiquitinase USP9x induces pre-B cell homeobox 1 (PBX1) degradation and thereby stimulates prostate cancer cell apoptosis
复制标题
抑制去泛素酶 USP9x 可诱导前 B 细胞同源盒 1 (PBX1) 降解，从而刺激前列腺癌细胞凋亡
DOI：
10.1074/jbc.ra118.006057
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发表时间：
2019-03-22
影响因子：
4.8
通讯作者：
Mao, Xinliang
中科院分区：
文献类型：
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作者：
Liu, Yan;Xu, Xiaofeng;Mao, Xinliang
化疗耐药性是晚期前列腺癌（PCa）有效治疗的主要障碍。更好地了解PCa化疗耐药的分子机制可以改善PCa患者的治疗。在本研究中，使用免疫组织化学，化学和沉淀分析与细胞从个人良性或恶性前列腺癌或建立PCa细胞系，我们发现，致癌转录因子前B细胞白血病同源框-1（PBX 1）促进PCa细胞增殖，并赋予抵抗常见的抗癌药物，如阿霉素和顺铂。我们观察到，遗传PBX 1敲除废除这种阻力，进一步的实验表明，PBX 1的稳定性是由泛素-蛋白酶体途径调节。为了直接探测该途径对PBX 1活性的影响，我们筛选了PBX 1特异性去泛素化酶（Dubs），发现泛素特异性肽酶9 X连接（USP 9 x）通过减弱其Lys-48连接的多聚泛素化与PBX 1蛋白相互作用并稳定PBX 1蛋白。此外，USP 9 x抑制剂WP 1130显著诱导PBX 1降解并促进PCa细胞凋亡。本研究的结果表明，PBX 1赋予PCa化学抗性，并将USP 9 x鉴定为PBX 1的Dub。我们得出结论，靶向USP 9 x/PBX 1轴可能是治疗晚期前列腺癌的潜在治疗策略。
Chemoresistance is a leading obstacle in effective management of advanced prostate cancer (PCa). A better understanding of the molecular mechanisms involved in PCa chemoresistance could improve treatment of patients with PCa. In the present study, using immune histochemical, chemistry, and precipitation assays with cells from individuals with benign or malignant prostate cancer or established PCa cell lines, we found that the oncogenic transcription factor pre-B cell leukemia homeobox-1 (PBX1) promotes PCa cell proliferation and confers to resistance against common anti-cancer drugs such as doxorubicin and cisplatin. We observed that genetic PBX1 knockdown abrogates this resistance, and further experiments revealed that PBX1 stability was modulated by the ubiquitin-proteasomal pathway. To directly probe the impact of this pathway on PBX1 activity, we screened for PBX1-specific deubiquitinases (Dubs) and found that ubiquitin-specific peptidase 9 X-linked (USP9x) interacted with and stabilized the PBX1 protein by attenuating its Lys-48–linked polyubiquitination. Moreover, the USP9x inhibitor WP1130 markedly induced PBX1 degradation and promoted PCa cell apoptosis. The results in this study indicate that PBX1 confers to PCa chemoresistance and identify USP9x as a Dub of PBX1. We concluded that targeting the USP9x/PBX1 axis could be a potential therapeutic strategy for managing advanced prostate cancer.