Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth.
Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth.
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作者：
Deng X;Shao G;Zhang HT;Li C;Zhang D;Cheng L;Elzey BD;Pili R;Ratliff TL;Huang J;Hu CD
蛋白精氨酸甲基转移酶5 （Protein arginine methyltransferase 5, PRMT5）是一种新兴的表观遗传酶，主要通过组蛋白H4R3、H3R8和H2AR3上精氨酸残基的对称二甲基化来抑制靶基因的转录。越来越多的证据表明，PRMT5可能作为一种致癌基因，通过几种肿瘤抑制因子的表观遗传失活来驱动癌细胞生长。在这里，我们提供的证据表明，PRMT5通过表观遗传激活前列腺癌细胞中雄激素受体（AR）的转录来促进前列腺癌细胞的生长。敲低PRMT5或特定抑制剂抑制PRMT5可降低AR的表达，抑制多种AR阳性而非AR阴性前列腺癌细胞的生长。值得注意的是，ar阳性LNCaP细胞中PRMT5的敲低完全抑制小鼠异种移植肿瘤的生长。分子分析表明，PRMT5结合到AR基因的近端启动子区域，并主要参与该区域H4R3对称二甲基化的富集。从机制上讲，PRMT5通过与Sp1（负责AR转录的主要转录因子）的相互作用被招募到AR启动子中，并与Brg1（一种依赖atp的染色质重塑剂）在AR基因的近端启动子区域形成复合物。PRMT5在前列腺癌组织中的表达显著高于良性前列腺增生组织，且PRMT5的表达在蛋白和mRNA水平上均与AR表达呈正相关。综上所述，我们的研究结果确定PRMT5是前列腺癌中AR的一种新的表观遗传激活因子。鉴于抑制AR转录活性或雄激素合成仍然是大多数现有抗雄激素药物的主要作用机制，我们的研究结果也提出了一种有趣的可能性，即靶向PRMT5可能代表了通过消除AR表达来治疗前列腺癌的新方法。
Protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3. Accumulating evidence suggests that PRMT5 may function as an oncogene to drive cancer cell growth by epigenetic inactivation of several tumor suppressors. Here, we provide evidence that PRMT5 promotes prostate cancer cell growth by epigenetically activating transcription of the androgen receptor (AR) in prostate cancer cells. Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR-positive, but not AR-negative, prostate cancer cells. Significantly, knockdown of PRMT5 in AR-positive LNCaP cells completely suppresses the growth of xenograft tumors in mice. Molecular analysis reveals that PRMT5 binds to the proximal promoter region of the AR gene and contributes mainly to the enriched symmetric dimethylation of H4R3 in the same region. Mechanistically, PRMT5 is recruited to the AR promoter by its interaction with Sp1, the major transcription factor responsible for AR transcription, and forms a complex with Brg1, an ATP-dependent chromatin remodeler, on the proximal promoter region of the AR gene. Furthermore, PRMT5 expression in prostate cancer tissues is significantly higher than that in benign prostatic hyperplasia tissues, and PRMT5 expression correlates positively with AR expression at both the protein and mRNA levels. Taken together, our results identify PRMT5 as a novel epigenetic activator of AR in prostate cancer. Given that inhibiting AR transcriptional activity or androgen synthesis remains the major mechanism of action for most existing anti-androgen agents, our findings also raise an interesting possibility that targeting PRMT5 may represent a novel approach for prostate cancer treatment by eliminating AR expression.