Neddylation inactivation represses androgen receptor transcription and inhibits growth, survival and invasion of prostate cancer cells
Neddylation inactivation represses androgen receptor transcription and inhibits growth, survival and invasion of prostate cancer cells
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Neddylation 失活抑制雄激素受体转录并抑制前列腺癌细胞的生长、存活和侵袭
DOI：
10.1016/j.neo.2020.02.002
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发表时间：
2020
期刊：
影响因子：
4.8
通讯作者：
Sun Yi
中科院分区：
文献类型：
--
作者：
Zhou Xiaochen;Han Sumin;Wilder-Romans Kari;Sun Grace Y.;Zhu Hong;Liu Xiaoqiang;Tan Mingjia;Wang Gongxian;Feng Felix Y.;Sun Yi
雄激素受体(AR)及其结构性活性变异体(AR-VS)与前列腺癌的进展和复发密切相关，是前列腺癌治疗的靶点。代谢修饰是否以及如何调节AR，以及这一潜在调节的治疗意义，是相对未被探索的研究领域。在这里，我们报告了药物抑制剂MLN4924或基于Lenti-shRNA的去核苷酸激活酶(NAE)的基因敲除选择性地抑制前列腺癌细胞的生长和存活，对正常前列腺上皮细胞的影响很小。MLN4924还显著抑制了前列腺癌细胞的侵袭能力。此外，与单一治疗相比，MLN4924与AR拮抗剂或去势联合使用显著增强了前列腺癌细胞的体外生长抑制和体内移植瘤模型中的肿瘤生长。机制上，MLN4924抑制AR/AR-V7及其下游靶基因的转录，阻断MMP2和MMP9的表达。综上所述，我们的研究表明，去分化途径正向调节AR/AR-V7转录，去分化抑制剂MLN4924具有治疗侵袭性前列腺癌的潜力。
Androgen receptor (AR) and its constitutively active variants (AR-Vs) have been extensively implicated in the progression and recurrence of prostate cancer, making them attractive targets in the treatment of this disease. Whether and how neddylation modification regulates AR, and the therapeutic implications of this potential regulation, are relatively unexplored areas of investigation. Here we report that neddylation inactivation by the pharmacological inhibitor MLN4924 or Lenti-shRNA-based genetic knockdown of neddylation activating enzyme (NAE) selectively suppressed growth and survival of prostate cancer cells with minor, if any, effect on normal prostate epithelial cells. MLN4924 also significantly suppressed the invasive capacity of prostate cancer cells. Furthermore, compared to monotherapy, the combination of MLN4924 with AR antagonist or castration significantly enhanced growth suppression of prostate cancer cellsin vitro, and tumor growth in anin vivoxenograft model. Mechanistically, MLN4924 repressed the transcription of AR/AR-V7 and its downstream targets, and blocked MMP2 and MMP9 expression. Taken together, our study reveals that the neddylation pathway positively regulates AR/AR-V7 transcription, and that the neddylation inhibitor MLN4924 has therapeutic potential for the treatment of aggressive prostate cancers.