Protein Arginine Methyltransferase 5 Promotes pICln-Dependent Androgen Receptor Transcription in Castration-Resistant Prostate Cancer.
Protein Arginine Methyltransferase 5 Promotes pICln-Dependent Androgen Receptor Transcription in Castration-Resistant Prostate Cancer.
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蛋白精氨酸甲基转移酶5促进去势抵抗性前列腺癌中pICln依赖性雄激素受体的转录
DOI：
10.1158/0008-5472.can-20-1228
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发表时间：
2020-11-15
期刊：
影响因子：
11.2
通讯作者：
Hu CD
中科院分区：
文献类型：
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作者：
Beketova E;Fang S;Owens JL;Liu S;Chen X;Zhang Q;Asberry AM;Deng X;Malola J;Huang J;Li C;Pili R;Elzey BD;Ratliff TL;Wan J;Hu CD
大多数晚期前列腺癌治疗旨在抑制雄激素受体（AR）信号传导。然而，AR再激活不可避免地将疾病进展为去势抵抗性前列腺癌（CRPC）。在这里，我们证明，蛋白质精氨酸甲基转移酶5（PRMT 5）的功能作为AR转录CRPC的表观遗传激活剂，需要与甲基体亚基pICln的合作。在体外和小鼠异种移植肿瘤中，靶向PRMT 5或pICln抑制CRPC细胞的生长。全长AR和AR-V7转录激活需要PRMT 5和pICln，但不需要MEP 50。这种转录激活伴随着PRMT 5介导的H4 R3在近端AR启动子处的对称二甲基化。此外，PRMT 5的敲低消除了pICln与AR近端启动子区域的结合（但反之亦然），表明PRMT 5将pICln募集到AR启动子以激活AR转录。在22 Rv 1细胞中的差异基因表达分析证实PRMT 5和pICln都调节雄激素信号通路。此外，PRMT 5和pICln蛋白表达与CRPC组织中的AR和AR-V7蛋白表达呈正相关，并且在多个公开可用的CRPC数据集中，它们的表达在mRNA水平上高度相关。我们的研究结果表明，靶向PRMT 5或pICln可通过抑制AR和AR剪接变体的表达来规避AR再激活，从而探索作为CRPC治疗的新疗法。
The majority of advanced prostate cancer therapies aim to inhibit androgen receptor (AR) signaling. However, AR reactivation inevitably drives disease progression to castration-resistant prostate cancer (CRPC). Here we demonstrate that protein arginine methyltransferase 5 (PRMT5) functions as an epigenetic activator of AR transcription in CRPC, requiring cooperation with a methylosome subunit pICln. In vitro and in xenograft tumors in mice, targeting PRMT5 or pICln suppressed growth of CRPC cells. Full-length AR and AR-V7 transcription activation required both PRMT5 and pICln but not MEP50. This activation of transcription was accompanied by PRMT5-mediated symmetric dimethylation of H4R3 at the proximal AR promoter. Further, knockdown of PRMT5 abolished the binding of pICln (but not vice versa) to the AR proximal promoter region, suggesting that PRMT5 recruits pICln to the AR promoter to activate AR transcription. Differential gene expression analysis in 22Rv1 cells confirmed that PRMT5 and pICln both regulate the androgen signaling pathway. Additionally, PRMT5 and pICln protein expression positively correlated with AR and AR-V7 protein expression in CRPC tissues and their expression was highly correlated at the mRNA level across multiple publicly available CRPC datasets. Our results suggest that targeting PRMT5 or pICln may be explored as a novel therapy for CRPC treatment by suppressing expression of AR and AR splice variants to circumvent AR reactivation.