Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar.
Flow Cytometry Core Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar.
J Cell Mol Med. 2021 Feb;25(3):1583-1600. doi: 10.1111/jcmm.16260. Epub 2021 Jan 18.
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.
精氨酸甲基转移酶 5（PRMT5）在许多侵袭性癌症中活性失调，其水平升高与肿瘤生长和存活增加有关。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表达，并且通过表观遗传沉默途径拮抗剂 DKK1 和 DKK3，促进 WNT/β-CATENIN 增殖信号，导致 c-MYC、CYCLIN D1 和 SURVIVIN 的表达增强。通过染色质免疫沉淀（ChIP）研究，我们发现 PRMT5 结合 WNT 拮抗剂 DKK1 和 DKK3 的启动子区域，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，使用特异性小分子抑制剂化合物 5（CMP5）抑制 PRMT5，可减少 PRMT5 募集以及 DKK1 和 DKK3 启动子区域 H3R8 和 H4R3 组蛋白的甲基化，从而导致 CYCLIN D1 和 SURVIVIN 的表达减少。此外，CMP5 单独或与 5-Azacytidine 和 Trichostatin A 联合治疗可恢复三阴性乳腺癌中 DKK1 和 DKK3 的表达。PRMT5 抑制还改变了乳腺癌细胞的生长特征并诱导其死亡。总之，这些结果表明 PRMT5 通过表观遗传沉默 WNT/β-CATENIN 途径拮抗剂 DKK1 和 DKK3 来控制乳腺癌细胞的生长，从而上调 WNT/β-CATENIN 增殖信号。
