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

Department of Oncological Sciences, Huntsman Cancer Institute
Cancer Research (Impact Factor: 9.33). 06/2011; 71(16):5579-87. DOI: 10.1158/0008-5472.CAN-11-0458
Source: PubMed


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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    • "PRMT5 is one of the most well-characterized family members with SDMA activity and catalyzes formation of SDMA in proteins with a glycine and arginine-rich motif [15]. PRMT5 was reported to regulate various cellular functions including apoptosis, Golgi structure, pluripotency, cell growth, and snRNP biosynthesis [16] [17] [18]. One important key marker of the PRMT5 activity is the symmetrical dimethylation of histone 3 arginine 8 (H3R8me2s) level. "
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    ABSTRACT: p53 is one of the most important tumor suppressor genes involved in human carcinogenesis. Although downstream targets of p53 and their biologic functions in cancer cells have been extensively investigated, it is still far from the full understanding. Here, we demonstrate that Late Cornified Envelope Group I (LCE1) genes, which are located in the LCE gene clusters encoding multiple well-conserved stratum-corneum proteins, are novel downstream targets of p53. Exogenous p53 overexpression using an adenoviral vector system significantly enhanced the expression of LCE1 cluster genes. We also observed induction of LCE1 expressions by DNA damage, which was caused by treatment with adriamycin or UV irradiation in a wild-type p53-dependent manner. Concordantly, the induction of LCE1 by DNA damage was significantly attenuated by the knockdown of p53. Among predicted p53-binding sites within the LCE1 gene cluster, we confirmed one site to be a p53-enhancer sequence by reporter assays. Furthermore, we identified LCE1 to interact with protein arginine methyltransferase 5 (PRMT5). Knockdown of LCE1 by specific small interfering RNAs significantly increased the symmetric dimethylation of histone H3 arginine 8, a substrate of PRMT5, and overexpression of LCE1F remarkably decreased its methylation level. Our data suggest that LCE1 is a novel p53 downstream target that can be directly transactivated by p53 and is likely to have tumor suppressor functions through modulation of the PRMT5 activity.
    Neoplasia (New York, N.Y.) 08/2014; 16(8). DOI:10.1016/j.neo.2014.07.008 · 4.25 Impact Factor
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    • "Epigenetic regulation plays an important role in oncogenesis, and histone modification has been recognized as one strategy for modifying epigenetic controls [25,26]. It has been shown in cell culture and in animal models that PRMT5 is an important epigenetic modifier of histone and non-histone proteins in lymphomas, breast, colorectal and lung cancer, and its overexpression is associated with aggressive phenotype in these models [14,17,25,27,28]. In this study, we further corroborate the previous findings by showing a statistically significant difference in PRMT5 mRNA expression between tumors and matched nonneoplastic lung tissues in surgically resected specimens. "
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    ABSTRACT: Protein arginine methyltransferase-5 (PRMT5) is a chromatin-modifying enzyme capable of methylating histone and non-histone proteins, and is involved in a wide range of cellular processes that range from transcriptional regulation to organelle biosynthesis. As such, its overexpression has been linked to tumor suppressor gene silencing, enhanced tumor cell growth and survival. Quantitative real-time polymerase chain reaction, Western immunoblot and immunohistochemistry were used to characterize PRMT5 expression in lung cancer cell lines and human tumors. Clinicopathological findings of tissue microarray based samples from 229 patients with non-small cell lung carcinomas (NSCLC) and 133 cases with pulmonary neuroendocrine tumors (NET) were analyzed with regard to nuclear and cytoplasmic PRMT5 expression. There was statistically significant difference in PRMT5 messenger RNA expression between tumors and nonneoplastic lung tissues. Immunoblot experiments showed abundant expression of PRMT5 and its symmetric methylation mark H4R3 in lung carcinoma but not in non-neoplastic human pulmonary alveolar and bronchial epithelial cell lines. More than two thirds of lung tumors expressed PRMT5. High levels of cytoplasmic PRMT5 were detected in 20.5% of NSCLC and in 16.5% of NET; high levels of nuclear PRMT5 were detected in 38.0% of NSCLC and 24.0% of NET. Cytoplasmic PRMT5 was associated with high grade in both NSCLC and pulmonary NET while nuclear PRMT5 was more frequent in carcinoid tumors (p < 0.05). The observed findings support the role of PRMT5 in lung tumorigenesis and reflect its functional dichotomy in cellular compartments.Virtual slide: The virtual slides for this article can be found here:
    Diagnostic Pathology 12/2013; 8(1):201. DOI:10.1186/1746-1596-8-201 · 2.60 Impact Factor
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    • "Coexpression of PRMT5 with programmed cell death 4 (PDCD4) influences tumor suppressor properties of PDCD4 resulting in accelerated tumor growth in a murine orthotopic model of breast cancer. In breast cancer patients whose tumors contain high level of PRMT5, elevated PDCD4 expression correlates with a worse outcome [66]. PRMT5 has also been implicated in tumorigenesis by its interaction with p53 protein [67], the most frequently inactivated gene in human cancers [68]. "
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    ABSTRACT: Protein arginine methylation is a novel posttranslational modification that plays a pivotal role in a variety of intracellular events, such as signal transduction, protein-protein interaction and transcriptional regulation, either by the direct regulation of protein function or by metabolic products originating from protein arginine methylation that influence nitric oxide (NO)-dependent processes. A growing body of evidence suggests that both mechanisms are implicated in cardiovascular and pulmonary diseases. This review will present and discuss recent research on PRMTs and the methylation of non-histone proteins and its consequences for the pathogenesis of various lung disorders, including lung cancer, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease and asthma. This article will also highlight novel directions for possible future investigations to evaluate the functional contribution of arginine methylation in lung homeostasis and disease.
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