PADI2-Mediated Citrullination Promotes Prostate Cancer Progression
PADI2-Mediated Citrullination Promotes Prostate Cancer Progression
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PADI2 介导的瓜氨酸化促进前列腺癌进展
DOI：
10.1158/0008-5472.can-17-0150
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发表时间：
2017-11-01
期刊：
影响因子：
11.2
通讯作者：
Han, Bo
中科院分区：
文献类型：
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作者：
Wang, Lin;Song, Guanhua;Han, Bo
长期雄激素剥夺治疗后的去势抵抗前列腺癌(CRPC)仍然是前列腺癌治疗的主要障碍。肽基精氨酸脱亚胺酶PADI2与慢性炎症性疾病和癌症有关。在这里，我们证明了PADI2是一个雄激素抑制基因，并且在CRPC中上调。PADI2的表达是前列腺癌细胞存活和细胞周期进展所必需的，在体内外去雄激素或去势条件下，PADI2促进了前列腺癌细胞的增殖。细胞质PADI2保护雄激素受体(AR)免受蛋白酶体介导的降解，并在组蛋白H3氨基酸残基R26的核易位和瓜氨酸化后促进AR与其靶基因的结合。相反，突变体PADI2 D180A未能影响AR的稳定性、核转位或转录活性。PADI2以一种依赖于其酶活性和核定位的方式介导AR控制，这与组蛋白H3瓜氨酸化增加有关。值得注意的是，联合应用PADI抑制剂氯-嘧啶和AR信号抑制剂苯扎鲁胺在体外抑制CRPC细胞增殖和抑制体内肿瘤生长方面具有协同作用。总体而言，我们的结果确定PADI2是前列腺癌进展中AR的关键介质，尤其是CRPC，他们建议PADI作为这种疾病的新的治疗靶点。(C)2017年AACR。
Onset of castration-resistance prostate cancer (CRPC) after long-term androgen deprivation therapy remains a major obstacle in the treatment of prostate cancer. The peptidylarginine deiminase PADI2 has been implicated in chronic inflammatory diseases and cancer. Here we show that PADI2 is an androgen-repressed gene and is upregulated in CRPC. PADI2 expression was required for survival and cell-cycle progression of prostate cancer cells, and PADI2 promoted proliferation of prostate cancer cells under androgen-deprived or castration conditions in vitro and in vivo. Cytoplasmic PADI2 protected the androgen receptor (AR) against proteasome-mediated degradation and facilitated AR binding to its target genes after nuclear translocation and citrullination of histone H3 amino acid residue R26. In contrast, mutant PADI2 D180A failed to affect AR stability, nuclear translocation, or transcriptional activity. PADI2 mediated AR control in a manner dependent on its enzymatic activity and nuclear localization, as correlated with increased histone H3 citrullination. Notably, coadministration of the PADI inhibitor Cl-Amidine and the AR signaling inhibitor enzalutamide synergized in inhibiting CRPC cell proliferation in vitro and tumor growth in vivo. Overall, our results establish PADI2 as a key mediator for AR in prostate cancer progression, especially CRPC, and they suggest PADI as novel therapeutic targets in this disease setting. (C) 2017 AACR.