The dual function of PRMT1 in modulating epithelial-mesenchymal transition and cellular senescence in breast cancer cells through regulation of ZEB1.
The dual function of PRMT1 in modulating epithelial-mesenchymal transition and cellular senescence in breast cancer cells through regulation of ZEB1.
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PRMT1通过调节ZEB1调节乳腺癌细胞上皮间质转化和细胞衰老的双重功能
DOI：
10.1038/srep19874
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发表时间：
2016-01-27
影响因子：
4.6
通讯作者：
Lu J
中科院分区：
文献类型：
--
作者：
Gao Y;Zhao Y;Zhang J;Lu Y;Liu X;Geng P;Huang B;Zhang Y;Lu J
虽然蛋白质精氨酸甲基转移酶1（PRMT1）参与肿瘤发生的报道，其在乳腺癌的进展和转移的作用尚未阐明。在这里，我们确定了PRMT1作为乳腺癌上皮间质转化（EMT）的关键调节因子。我们发现PRMT1诱导的EMT程序赋予人乳腺上皮细胞癌症干细胞特性。此外，PRMT1促进了乳腺癌细胞的迁移和侵袭行为。我们还证明了乳腺癌细胞中PRMT1表达的消除减轻了小鼠体内模型中的转移。此外，PRMT1的敲除阻止了G1四倍体的细胞生长并诱导细胞衰老。从机制上讲，PRMT1通过介导组蛋白H4的精氨酸3（H4R3me2as）在ZEB1启动子处的不对称二甲基化来激活其转录，从而影响EMT过程和细胞衰老，表明这种表观遗传控制在EMT和衰老中的重要作用。因此，我们揭示了PRMT1在调节EMT和衰老调节ZEB1中的双重功能。这一发现指出PRMT1作为预防转移和抑制恶性乳腺癌患者癌细胞生长的双重治疗靶点的潜在价值。
Although the involvement of protein arginine methyltransferase 1 (PRMT1) in tumorigenesis has been reported, its roles in breast cancer progression and metastasis has not been elucidated. Here we identified PRMT1 as a key regulator of the epithelial-mesenchymal transition (EMT) in breast cancer. We showed that the EMT program induced by PRMT1 endowed the human mammary epithelial cells with cancer stem cell properties. Moreover, PRMT1 promoted the migratory and invasive behaviors in breast cancer cells. We also demonstrated that abrogation of PRMT1 expression in breast cancer cells abated metastasisin vivoin mouse model. In addition, knockdown of PRMT1 arrested cell growth in G1 tetraploidy and induced cellular senescence. Mechanistically, PRMT1 impacted EMT process and cellular senescence by mediating the asymmetric dimethylation of arginine 3 of histone H4 (H4R3me2as) at the ZEB1 promoter to activate its transcription, indicating the essential roles of this epigenetic control both in EMT and in senescence. Thus, we unraveled a dual function of PRMT1 in modulation of both EMT and senescenceviaregulating ZEB1. This finding points to the potent value of PRMT1 as a dual therapeutic target for preventing metastasis and for inhibiting cancer cell growth in malignant breast cancer patients.