Peptidylargininedeiminase 1 (PAD1) catalyzes protein for citrullination, and this activity has been linked to the epidermal cornification. However, a role for PAD1 in tumorigenesis, including breast cancers has not been previously explored. Here we first showed that PAD1 is overexpressed in human triple negative breast cancer (TNBC). In cultured cells and xenograft mouse models, PAD1 depletion or inhibition reduced cell proliferation, suppressed epithelial-mesenchymal transition, and prevented metastasis of MDA-MB-231 cells. These changes were correlated with a dramatic decrease in MMP2/9 expression. Furthermore, ERK1/2 and P38 MAPK signaling pathways are activated upon PAD1 silencing. Treatment with MEK1/2 inhibitor in PAD1 knockdown cells significantly recovered MMP2 expression, while inhibiting P38 activation only slightly elevated MMP9 levels. We then showed that PAD1 interacts with and citrullinates MEK1 thereby disrupting MEK1-catalyzed ERK1/2 phosphorylation, thus leading to the MMP2 overexpression. Collectively, our data indicate that PAD1 appears to promote tumorigenesis by regulating MEK1-ERK1/2-MMP2 signaling in TNBC. These results also raise the possibility that PAD1 may function as an important new biomarker for TNBC tumors and suggest that PAD1-specific inhibitors could potentially be utilized to treat metastatic breast cancer.

中文翻译：

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PAD1通过调节MEK1-ERK1 / 2-MMP2信号传导促进三阴性乳腺癌细胞上皮-间质转化和转移。

肽基精氨酸亚胺酶1（PAD1）催化蛋白质进行瓜氨酸化，并且该活性与表皮角质化有关。但是，PAD1在包括乳腺癌在内的肿瘤发生中的作用尚未得到探讨。在这里，我们首先显示PAD1在人类三阴性乳腺癌（TNBC）中过表达。在培养的细胞和异种移植小鼠模型中，PAD1的消耗或抑制会减少细胞增殖，抑制上皮-间质转化，并防止MDA-MB-231细胞转移。这些变化与MMP2 / 9表达的急剧下降有关。此外，ERK1 / 2和P38 MAPK信号通路在PAD1沉默后被激活。在PAD1敲低细胞中用MEK1 / 2抑制剂治疗可显着恢复MMP2表达，而抑制P38激活仅使MMP9水平略有升高。然后，我们表明PAD1与MEK1相互作用并瓜氨酸化，从而破坏了MEK1催化的ERK1 / 2磷酸化，从而导致MMP2过表达。总体而言，我们的数据表明PAD1似乎通过调节TNBC中的MEK1-ERK1 / 2-MMP2信号传导来促进肿瘤发生。这些结果也增加了PAD1可能作为TNBC肿瘤的重要新生物标志物的可能性，并暗示PAD1特异性抑制剂可潜在地用于治疗转移性乳腺癌。