Protein arginine methyltransferase 5 (PRMT5) activity is dysregulated in many aggressive cancers and its enhanced levels are associated with increased tumour growth and survival. However, the role of PRMT5 in breast cancer remains underexplored. In this study, we show that PRMT5 is overexpressed in breast cancer cell lines, and that it promotes WNT/β‐CATENIN proliferative signalling through epigenetic silencing of pathway antagonists, DKK1 and DKK3, leading to enhanced expression of c‐MYC, CYCLIN D1 and SURVIVIN. Through chromatin immunoprecipitation (ChIP) studies, we found that PRMT5 binds to the promoter region of WNT antagonists, DKK1 and DKK3, and induces symmetric methylation of H3R8 and H4R3 histones. Our findings also show that PRMT5 inhibition using a specific small molecule inhibitor, compound 5 (CMP5), reduces PRMT5 recruitment as well as methylation of H3R8 and H4R3 histones in the promoter regions of DKK1 and DKK3, which consequently results in reduced expression CYCLIN D1 and SURVIVIN. Furthermore, CMP5 treatment either alone or in combination with 5‐Azacytidine and Trichostatin A restored expression of DKK1 and DKK3 in TNBCs. PRMT5 inhibition also altered the growth characteristics of breast cancer cells and induced their death. Collectively, these results show that PRMT5 controls breast cancer cell growth through epigenetic silencing of WNT/β‐CATENIN pathway antagonists, DKK1 and DKK3, resulting in up‐regulation of WNT/β‐CATENIN proliferative signalling.

中文翻译：

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蛋白精氨酸甲基转移酶 5 (PRMT5) 通过 DKK1 和 DKK3 的表观遗传沉默激活乳腺癌细胞中的 WNT/β-catenin 信号

蛋白质精氨酸甲基转移酶 5 (PRMT5) 活性在许多侵袭性癌症中失调，其水平升高与肿瘤生长和存活率增加有关。然而，PRMT5 在乳腺癌中的作用仍未得到充分探索。在这项研究中，我们表明 PRMT5 在乳腺癌细胞系中过度表达，并且它通过通路拮抗剂DKK1和DKK3 的表观遗传沉默促进 WNT/β-CATENIN 增殖信号传导，导致c-MYC、CYCLIN D1和生存。通过染色质免疫沉淀 (ChIP) 研究，我们发现 PRMT5 与 WNT 拮抗剂DKK1和DKK3的启动子区域结合，并诱导 H3R8 和 H4R3 组蛋白的对称甲基化。我们的研究结果还表明，PRMT5抑制使用特定的小分子抑制剂，化合物5（CMP5），降低PRMT5招募以及在启动子区域H3R8和H4R3组蛋白的甲基化DKK1和DKK3，这因此导致降低的表达细胞周期蛋白D1和生存。此外，CMP5 单独处理或与 5-氮杂胞苷和曲古菌素 A 联合处理可恢复DKK1和DKK3 的表达在 TNBC 中。PRMT5 抑制还改变了乳腺癌细胞的生长特征并诱导它们死亡。总的来说，这些结果表明 PRMT5 通过 WNT/β-CATENIN 通路拮抗剂 DKK1 和 DKK3 的表观遗传沉默来控制乳腺癌细胞的生长，导致 WNT/β-CATENIN 增殖信号的上调。