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: 9.28). 06/2011; 71(16):5579-87. 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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    • "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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