PRMT7 Induces The Epithelial-to-mesenchymal Transition And Promotes Breast Cancer Metastasis

Breast cancer is the most common malignant disease in women worldwide. In recent years, breast cancer has also become the most common tumor in Chinese women. By 2008, cases in China account for 12.2% of the world’s newly diagnosed breast carcinomas and 9.6% of the deaths from breast cancer. Noticeably, breast cancer metastasis leads to 90% of the mortality from solid tumors. The distant metastasis of breast cancer is an extremely complicated process, which involves the infiltration of primary cancer cells into blood circulation, and formation of metastatic colonization in new tumor microenvironment. However, breast cancer is a heterogeneous disease, and can be classified into four subtypes, i.e., luminal, basal-like, HER2+, and normal breast-like. This heterogeneity ultimately brings about the risk in evaluating breast cancer metastasis and the difficulty in therapy.The epithelial-to-mesenchymal transition(EMT) is referred to changes in cell phenotypes from epithelial to mesenchymal states under the given physiological or pathological conditions, mainly characterized by the loss of cell surface adhesion moleculars(such as E-cadherion), loss of cell polarity, cytoskeleton remodeling, enhanced cell migration and invasion capabilities. EMT has initially been recognized as a normal physiological activity in embryonic development. Subsequently, it has been found that EMT plays a pivotal role in wound healing, inflammation, tissue remodeling, and tumor metastasis. EMT behavior in tumor cells directly leads to enhanced invasion, thus EMT is frequently considered as one of the initial steps of tumor cell metastasis. At the molecular level, loss of E-cadherin expression is the most predominant hallmark of EMT. Besides, many transcription factors, such as Snail, Twist, ZEB1, ZEB2, and FOXC2, have been shown to directly or indirectly repress the E-cadherin promoter activity and subsequently to induce EMT. Recently, there have been some hints that epigenetic modifications are involved in the regulation of E-cadherin transcription. It has been shown that histone deacetylase1/2(HDAC1/2), histone demethylase LSD1, histone methyltransferases Suv39H1 and G9 a, and DNA methyltransferases(DNMTs) can repress E-cadherin gene transcription. Moreover, this epigenetic modification dysregulation is relevant to oncogenesis; and studies in this field will hopefully provide a greater mechanistic insight into human tumorigenesis and cancer metastasis.PRMT7 belongs to the type II methyltransferase family, capable of generating symmetric dimethyl-arginine(SDMA) modifications of histone and non-histone. It has been indicated that PRMT7 may participate in a variety of physiologic processes, including male imprinted gene methylation, Sn RNP assembly, DNA damage repair, and cellular differentiation. However, whether and how PRMT7 is involved in tumorigenesis and metastasis is currently unclear. Here our IHC data demonstrate that PRMT7 expresses at higher levels in breast carcinoma tissues, meanwhile, the analysis in Oncomine database further confirms this conclusion. At the cellular level, we discover that PRMT7 expresses at high level in malignant breast cancer cells, and ectopic PRMT7 overexpression mediates EMT and metastasis in vitro and in vivo. In the process of overexpression PRMT7-induced EMT of breast cancer cells, E-cadherin and other epithelial markers reduce significantly, along with the upregulation of N-cadherin and other mesenchymal markers. Moreover, we detect that PRMT7 can inhibit the transcriptional activity of the epithelial marker E-cadherin, and YY1 interacts with PRMT7 and HDAC3 directly, which is essential for linking the two proteins to E-cadherin promoter. In the process, we show that a dramatic elevation of PRMT7-generated H4R3me2 s and concomitant reduction of H3K4me3, H3 Ac and H4 Ac occur at E-cadherin promoter. On the contrary, depletion of PRMT7 restores E-cadherin expression by repressing H4R3me2 s and by increasing H3K4me3 and H4 Ac at the E-cadherin promoter.Data arising from this study defines PRMT7 as an important inducer of breast cancer metastasis. At the same time, we also uncover a new epigenetic regulation mechanism of EMT in breast cancer and metastasis. This study provides basis for the development of PRMT7-targeted therapeutic intervention for metastatic breast carcinoma.