Epithelial-to-mesenchymal transition (EMT) enables metastasis. E-cadherin loss is a hallmark of EMT, but there remains an incomplete understanding of the epigenetics of this process. The protein arginine methyltransferase PRMT7 functions in various physiologic processes, including mRNA splicing, DNA repair, and neural differentiation, but its possible roles in cancer and metastasis have not been explored. In this report, we show that PRMT7 is expressed at higher levels in breast carcinoma cells and that elevated PRMT7 mediates EMT and metastasis. PRMT7 could inhibit the expression of E-cadherin by binding to its proximal promoter in a manner associated with altered histone methylation, specifically with elevated H4R3me2s and reduced H3K4me3, H3Ac, and H4Ac, which occurred at the E-cadherin promoter upon EMT induction. Moreover, PRMT7 interacted with YY1 and HDAC3 and was essential to link these proteins to the E-cadherin promoter. Silencing PRMT7 restored E-cadherin expression by repressing H4R3me2s and by increasing H3K4me3 and H4Ac, attenuating cell migration and invasion in MDA-MB-231 breast cancer cells. Overall, our results define PRMT7 as an inducer of breast cancer metastasis and present the opportunity for applying PRMT7-targeted therapeutics to treat highly invasive breast cancers. Cancer Res; 74(19); 5656–67. ©2014 AACR.

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Epithelial-mesenchymal transition is a change of cellular plasticity critical for embryonic development and tumor metastasis. CDK5 is a proline-directed serine/threonine kinase playing important roles in cancer progression. Here we show that CDK5 is commonly overexpressed and significantly correlated with several poor prognostic parameters of breast cancer. We found that CDK5 participated in TGF-β1-induced EMT. In MCF10A, TGF-β1 upregulated the CDK5 and p35 expression, and CDK5 knockdown inhibited TGF-β1-induced EMT. CDK5 overexpression also exhibited a potential synergy in promoting TGF-β1-induced EMT. In mesenchymal breast cancer cells MDA-MB-231 and BT549, CDK5 knockdown suppressed cell motility and tumorigenesis. We further demonstrated that CDK5 modulated cancer cell migration and tumor formation by regulating the phosphorylation of FAK at Ser-732. Therefore, CDK5-FAK pathway, as a downstream step of TGF-β1 signaling, is essential for EMT and motility in breast cancer cells. This study implicates the potential value of CDK5 as a molecular marker for breast cancer.

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.

Previous studies have shown an anticancer effect of vitamin D, but the mechanisms underlying this action have not been fully explored. Here we show that 1,25‐dihydroxyvitamin D3 (VD3, the active form of vitamin D) significantly promoted apoptosis in the undifferentiated gastric cancer cell line HGC‐27, and this was accompanied by a concurrent increase in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression on VD3 treatment. In contrast, knockdown of PTEN expression by stable transfection of PTEN small interfering RNA greatly decreased the apoptosis rate. We further demonstrated that VD3 induced PTEN expression through vitamin D receptor. In addition, our evidence showed that vitamin D receptor, Egr‐1 and p300 induced PTEN expression in a synergistic fashion. Furthermore, we found that the histone deacetylase inhibitors trichostatin A and sodium butyrate and the methylation inhibitor 5‐aza‐2′‐deoxycytidine played important roles in vitamin D‐induced apoptosis through PTEN upregulation. The data presented in this article suggest potential benefits of vitamin D in gastric cancer therapies in association with the use of trichostatin A/sodium butyrate and 5‐aza‐2′‐deoxycytidine.Structured digital abstract MINT‐7306489, MINT‐7306501, MINT‐7306512: P300 (uniprotkb:Q09472) physically interacts (MI:0914) with VDR (uniprotkb:P11473) and EGR1 (uniprotkb:P18146) by anti bait coimmunoprecipitation (MI:0006)