Protein Arginine Methyltransferase 5 Accelerates Tumor Growth by Arginine Methylation of the Tumor Suppressor Programmed Cell Death 4

ArticleinCancer Research 71(16):5579-87 · June 2011with14 Reads
Impact Factor: 9.33 · DOI: 10.1158/0008-5472.CAN-11-0458 · Source: PubMed
Abstract

Programmed cell death 4 (PDCD4) has been described as a tumor suppressor, with high expression correlating with better outcomes in a number of cancer types. Yet a substantial number of cancer patients with high PDCD4 in tumors have poor survival, suggesting that oncogenic pathways may inhibit or change PDCD4 function. Here, we explore the significance of PDCD4 in breast cancer and identify protein arginine methyltransferase 5 (PRMT5) as a cofactor that radically alters PDCD4 function. Specifically, we find that coexpression of PDCD4 and PRMT5 in an orthotopic model of breast cancer causes accelerated tumor growth and that this growth phenotype is dependent on both the catalytic activity of PRMT5 and a site of methylation within the N-terminal region of PDCD4. In agreement with the xenograft model, elevated PDCD4 expression was found to correlate with worse outcome within the cohort of breast cancer patients whose tumors contain higher levels of PRMT5. These results reveal a new cofactor for PDCD4 that alters its tumor suppressor functions and point to the utility of PDCD4/PRMT5 status as both a prognostic biomarker and a potential target for chemotherapy.

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    • "Some studies have found a task for PDCD4 as a tumor oppressor that is missed in definite aggressive malignancies [21]. Surprisingly, recent evidence also proved that the mission of PDCD4 can be changed by the cofactor protein arginine methyltransferase 5 (PRMT5) and that arginine methylation of PDCD4 leads to progression of malignant transformation [22]. Therefore, there is strong evidence that PDCD4 has a serious role in the regulation of carcinogenesis and that its deregulation has significant outcome in cell growth and carcinogenesis. "
    [Show abstract] [Hide abstract] ABSTRACT: AIM: To determine the relation between serum microRNAs and apoptotic markers as regards development of HCC to understand the underlying mechanism of HCV related hepatocarcinogenesis. PATIENTS AND METHODS: A total of 65 serum samples (25 samples from controls, 20 samples from hepatitis and 20 samples from HCC patients) were collected for miRNAs (mir 21, mir 199-a, and mir 155) detection. Human Programmed cell death protein-4 (PDCD-4) and Human Cytochrome-C (CYT-C) were determined. RESULTS: miRNAs 21 and 155 were over expressed in sera of patients with HCC compared to patients with chronic hepatitis (p < 0.0001). While serum means values of miR 199a was significantly decreased among HCC group patients when compared to patients with chronic hepatitis (p < 0.0001). The serum levels of PCDC4 and CYTC were increased in patients with HCC when compared to chronic hepatitis patients. They were also increased in patients with chronic hepatitis when compared to controls (p < 0.05, significant). There was direct correlations between apoptotic markers and oncomirs miRNAs 21 and 155 while apoptotic markers were inversely correlated with miRNA 199-a. CONCLUSION: Both microRNAs and apoptotic markers have roles in HCC pathogenesis. It seems that oncogenic microRNAs induce liver carcinogenesis in HCV patients irrespective of suppression of apoptosis.AIM: To determine the relation between serum microRNAs and apoptotic markers as regards development of HCC to understand the underlying mechanism of HCV related hepatocarcinogenesis. PATIENTS AND METHODS: A total of 65 serum samples (25 samples from controls, 20 samples from hepatitis and 20 samples from HCC patients) were collected for miRNAs (mir 21, mir 199-a, and mir 155) detection. Human Programmed cell death protein-4 (PDCD-4) and Human Cytochrome-C (CYT-C) were determined. RESULTS: miRNAs 21 and 155 were over expressed in sera of patients with HCC compared to patients with chronic hepatitis (p < 0.0001). While serum means values of miR 199a was significantly decreased among HCC group patients when compared to patients with chronic hepatitis (p < 0.0001). The serum levels of PCDC4 and CYTC were increased in patients with HCC when compared to chronic hepatitis patients. They were also increased in patients with chronic hepatitis when compared to controls (p < 0.05, significant). There was direct correlations between apoptotic markers and oncomirs miRNAs 21 and 155 while apoptotic markers were inversely correlated with miRNA 199-a. CONCLUSION: Both microRNAs and apoptotic markers have roles in HCC pathogenesis. It seems that oncogenic microRNAs induce liver carcinogenesis in HCV patients irrespective of suppression of apoptosis.
    Full-text · Article · Mar 2016
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    • "Moreover, the process of methylation on arginine residues has been linked to tumoural development. For example, methylation of the tumour suppressor protein programmed cell death protein 4 (PDC4) by PRMT5 was involved in breast tumourigenesis [14]. Methylation of ERα by PRMT1 associated with oestrogen non-genomic signaling activation is increased in aggressive breast cancer [15]. "
    [Show abstract] [Hide abstract] ABSTRACT: Protein arginine methylation is a common post translational modification that regulates protein properties. This modification is carried out by a family of nine arginine methyltransferases (PRMTs). Arginine methylation has already been linked to tumourigenesis as overexpression of these enzymes was associated with various cancers, notably in breast cancers. Since the Jumonji Domain Containing 6 protein (JMJD6) possesses an arginine demethylase activity able to remove the methyl mark, we wanted to assess its potential role in breast tumourigenesis. The expression of the protein by tissue microarray immunohistochemical staining was performed on a cohort of 133 breast tumours. Using cell lines stably overexpressing or knocked down for JMJD6, we evaluated its role on cell proliferation, cell migration, colony formation and mice tumour xenografts. The analysis of JMJD6 expression in a cohort of breast tumour samples indicates that JMJD6 was highly expressed in aggressive breast tumours. Moreover, high expression of JMJD6 was associated with poor disease-free survival of patients in this cohort. JMJD6 silencing in breast tumoural cells promotes certain characteristics of tumourigenesis including proliferation, migration in vitro, and tumour growth in vivo. These effects are dependent on its demethylase activity as an enzymatic dead mutant lost these properties. Although JMJD6 displays anti-tumoral properties in cell lines, its expression in breast tumours may be a marker of poor prognosis, suggesting that its function could be altered in breast cancer.
    Full-text · Article · May 2015 · PLoS ONE
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    • "tumor suppressor which is known to function in pro-apoptotic pathways in breast cancer cells [149, 150] and is essential for the growth of lung cancer cells [123, 135] . The programmed cell death 4 (PDCD4) tumor suppressor protein conversely functions to promote cell growth and tumor formation when overexpressed with PRMT5 [126, 151]. Menin/MEN1 interacts with PRMT5 to alter its activity, and cancer-associated Menin mutations appear to block this interaction, possibly altering the targeting of PRMT5 and promoting tumorigenesis [110, 111]. "
    [Show abstract] [Hide abstract] ABSTRACT: Post-translational arginine methylation is responsible for regulation of many biological processes. The protein arginine methyltransferase 5 (PRMT5, also known as Hsl7, Jbp1, Skb1, Capsuleen, or Dart5) is the major enzyme responsible for mono- and symmetric dimethylation of arginine. An expanding literature demonstrates its critical biological function in a wide range of cellular processes. Histone and other protein methylation by PRMT5 regulate genome organization, transcription, stem cells, primordial germ cells, differentiation, the cell cycle, and spliceosome assembly. Metazoan PRMT5 is found in complex with the WD-repeat protein MEP50 (also known as Wdr77, androgen receptor coactivator p44, or Valois). PRMT5 also directly associates with a range of other protein factors, including pICln, Menin, CoPR5 and RioK1 that may alter its subcellular localization and protein substrate selection. Protein substrate and PRMT5-MEP50 post-translation modifications induce crosstalk to regulate PRMT5 activity. Crystal structures of C. elegans PRMT5 and human and frog PRMT5-MEP50 complexes provide substantial insight into the mechanisms of substrate recognition and procession to dimethylation. Enzymological studies of PRMT5 have uncovered compelling insights essential for future development of specific PRMT5 inhibitors. In addition, newly accumulating evidence implicates PRMT5 and MEP50 expression levels and their methyltransferase activity in cancer tumorigenesis, and, significantly, as markers of poor clinical outcome, marking them as potential oncogenes. Here, we review the substantial new literature on PRMT5 and its partners to highlight the significance of understanding this essential enzyme in health and disease.
    Full-text · Article · Feb 2015 · Cellular and Molecular Life Sciences CMLS
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